https://phys.org/news/2025-06-unraveling-g4-cells-untie-dna.html

"Not all DNA looks like the familiar twisted ladder. Sometimes, parts of our genetic code fold into unusual shapes. One such structure, the G-quadruplex (G4), looks like a knot. These knots can play important roles in turning genes on or off. But if not untangled in time, they can harm our genome.

***

"Human DNA is usually shaped like a double helix. However, under certain conditions, a single strand of DNA can fold into a G-quadruplex (G4) structure, which looks like a knot. These knots often form in regions with many guanine (G) bases. They help regulate important processes like transcription, where DNA is copied into RNA.

"But G4s are double-edged swords. While they help with gene regulation, if they are not untangled in time, they may cause mutations, disrupt gene expression, and even lead to cancer or early aging. Therefore, cells need tools to untie these knots quickly and efficiently.

***

"...the researchers uncovered a surprising new role for RNA molecules. "With the help of proteins known for their role in DNA repair, RNA binds to the DNA strand opposite the G4 structure, forming a structure called a "G-loop." This G-loop structure is an important intermediate in the untangling mechanism and protects the genome from breaking down" says first author Koichi Sato.

"Although RNA is best known for its function in protein production through translation, this mechanism adds a previously unrecognized role for RNA in genome protection.

"The G-loop acts like a landing pad for additional proteins. These proteins untie the G4 knot, break apart the G-loop and convert the DNA to its normal double helix shape. Thanks to a collaboration with Simon Elsässer and Jing Lyu from the Karolinska Institute, the team discovered that the G-loop helps untie G4 knots across the entire genome.

"
We were surprised to find that G4s are recognized as DNA lesions, even without real DNA damage," explains group leader Puck Knipscheer. The G-loop brings in proteins that usually fix DNA damage. But here, the cell treats the G4 structure as if it were broken DNA, triggering a DNA damage response. This allows the cell to act fast and prevent serious problems later.

"Even better, the process renews the surrounding DNA and removes harmful modifications.

***

"...the team shows how important this mechanism is for cell health. When it fails, G4s build up and cause serious problems when the DNA needs to be copied before cell division. This results in DNA breaks and blocks cell growth.

Comment: a control and regulating process with repair all in one. If ever there was a clue pointing to design this is it.

https://mail.google.com/mail/u/0/#inbox/FMfcgzQbfLdjzdWwnrlRNsWLRrjpBNnL

"Starting around 10,000 years ago when people first settled in regions of the Andes mountains, gene variants arose that code for enzymes to break down arsenic in the liver (it leaches into groundwater in some regions there).
Around 4,500 years ago a gene spread in Europe and South Asia enabling people to digest milk past childhood.

"Around 8,500 years ago early farmers spread an allele (a version of a gene) that helped them synthesize long-chain polyunsaturated fatty acids from plant-based foods—these fatty acids are crucial for forming cell membranes, especially in the brain, and normally would only be obtained by eating meat.

"Why this matters: Such shifts in our ancestral DNA were among dozens in humans, based on new genetic analyses. For much of the 21st century, evolutionary biologists have assumed that humans evolved at a leisurely pace in recent millennia. But genetic studies suggest that H. sapiens experienced many major episodes of natural selection."

Comment: solidifies the point, we are very very adaptable.

https://www.sciencealert.com/humans-are-evolving-right-in-front-of-our-eyes-on-the-tibe...

"'Adaptation to high-altitude hypoxia is fascinating because the stress is severe, experienced equally by everyone at a given altitude, and quantifiable," anthropologist Cynthia Beall of Case Western Reserve University in the US told ScienceAlert.

"'It is a beautiful example of how and why our species has so much biological variation."

***

"To unlock this discovery, the researchers delved into one of the markers of what we call evolutionary fitness: reproductive success. Women who deliver live babies are those who pass on their traits to the next generation.

"The traits that maximize an individual's success in a given environment are most likely to be found in women who are able to survive the stresses of pregnancy and childbirth.

***

"Among the things they measured were levels of hemoglobin, the protein in red blood cells responsible for delivering oxygen to tissues. They also measured how much oxygen was being carried by the hemoglobin. Interestingly, the women who demonstrated the highest rate of live births had hemoglobin levels that were neither high nor low, but average for the testing group.

"But the oxygen saturation of the hemoglobin was high. Together, the results suggest that the adaptations are able to maximize oxygen delivery to cells and tissues without thickening the blood – a result that would place more stress on the heart as it struggles to pump a higher viscosity fluid more resistant to flow.

***

"Taken all together, these traits increase the rate of oxygen transport and delivery, enabling the human body to make the most of the low oxygen in the air respired."

Comment: this article has a headline that touts evolution happening: "Humans Are Evolving Right in Front of Our Eyes on The Tibetan Plateau". Wrong! They are adapting to severe conditions. Homans have an enormous adaptive ability.

https://www.sciencedaily.com/releases/2025/04/250414124702.htm

"The publication of two papers demonstrates how work led by laboratories from the Department of Cancer and Genomic Sciences, and School of Biosciences at the University of Birmingham has made strides in understanding how the repair process is correctly orchestrated.

***

"Our cells protect their DNA by constantly monitoring and repairing any damage. When DNA is damaged, internal signals activate within the cell to pinpoint the damage and recruit specialised proteins -- DNA repair "machines" -- to fix the break. This repair process must be tightly regulated to ensure the correct proteins arrive in the right amounts and in the correct sequence.

***

"The first study, published in Nature Communications today (Monday 14 April), identifies a "twisting switch" that helps turn off early repair signals by altering the shape of proteins. Without the switch, repair signals stay active too long, disrupting the correct sequencing of the repair machine arrival at and exit from the broken site so that DNA repair is blocked.

"The discovery of the twisting switch resolves a long-standing question about how the DNA repair protein RNF168, which has a tendency to cause uncontrolled signalling, is switched off. The paper outlines a four-step process that removes RNF168 from chromatin, preventing excessive DNA damage signals and demonstrates that without these steps, cells become hypersensitive to radiation.

"A second study published in Molecular Cell identified that a component previously assumed to have very little function in cells, SUMO4, has a crucial role to help prevent the DNA damage signal from being overwhelmed.

"Without SUMO4, there is an excess of one type of signalling, disrupting other signals and preventing some repair proteins from reaching the damaged site. As a result, DNA repair fails. The significance of this research comes from the way it challenges earlier assumptions about the importance of the SUM04 protein."

Comment: think about the timing of developments in DNA. Could it have appeared without these repair elements present at the same time? Very doubtful. A DNA system without a repair mechanism present would not have survived. DNA damage is a natural occurrence, so damage control is a necessity. More evidence for design.

https://www.sciencedaily.com/releases/2025/04/250410160707.htm

"Bioinformaticians have established that the genes in bacterial genomes are arranged in a meaningful order. They describe that the genes are arranged by function: If they become increasingly important at faster growth, they are located near the origin of DNA replication. Accordingly, their position influences how their activity changes with the growth rate.

***

"In the journal Science, they describe that the genes are arranged by function: If they become increasingly important at faster growth, they are located near the origin of DNA replication. Accordingly, their position influences how their activity changes with the growth rate.

***

"When bacteria replicate their genetic material in preparation for cell division, the process starts at a specific point on the bacterial chromosome and continues along the chromosome in both directions.

"Dr Xiao-Pan Hu from HHU, lead author of the study now published in Science: "For a short time during this process, there are more copies of those genes located closer to the origin of replication than of those located further away. Accordingly, genes close to the origin can be read more frequently."

"'We have established that these genes are particularly important for cell growth -- e.g. those whose products assemble the proteins of the bacteria," adds Professor Lercher, corresponding author of the study.

"By contrast, genes rarely needed in the growth phases are usually found at the opposing end of the chromosome, where they are duplicated late in the process.

***

"They found that the positioning of the genes along the chromosome must have arisen as a consequence of evolutionary pressure, as those bacteria that can grow particularly quickly as a result of optimally placed genes have an evolutionary advantage.

"Dr Hu: "We now understand better how bacteria control their genes. The results really surprised us. They provide an excellent explanation of an important aspect of bacterial evolution: The right genomic positioning gave the bacteria existing today an advantage over their rivals.'"

Comment: if this developed by natural trial and error would bacteria every survive? Why are we surprised by finding logical designs in every research into how life works?

https://phys.org/news/2025-03-critical-enzyme-potentially-dangerous-genes.html

"You may have heard of the fantastic-sounding "dark side of the genome." This poorly studied fraction of DNA, known as heterochromatin, makes up around half of your genetic material, and scientists are now starting to unravel its role in your cells.

"For more than 50 years, scientists have puzzled over the genetic material contained in this "dark DNA." But there's a growing body of evidence showing that its proper functioning is critical for maintaining cells in a healthy state. Heterochromatin contains tens of thousands of units of dangerous DNA, known as "transposable elements" (or TEs). TEs remain silently "buried" in heterochromatin in normal cells—but under many pathological conditions they can "wake up" and occasionally even "jump" into our regular genetic code.

"And if that change benefits a cell? How wonderful! Transposable elements have been co-opted for new purposes through evolutionary history—for instance the RAG genes in immune cells and the genes required for driving the development of the placenta and mammalian evolution have been derived from TEs.

"But TEs may also wreak havoc on our health. In just the last few years, scientists have linked heterochromatin weakening to aging, premalignancy, cancer, and autoimmune disease.

***

"'When heterochromatin loses its normal suppressive function, TEs escape and in parallel, the health of cells declines."

"The new study reveals a remarkable way that cells keep us safe from TEs gone wild. The researchers found that cells have taken advantage of an entire protein network to repress TE activity and keep themselves healthy.

***

"Meet O-GlcNAc transferase (OGT), an enzyme at the heart of many essential cellular functions. According to the new study, OGT is also a lead choreographer when it comes to suppressing TEs and keeping gene expression running smoothly.

"For the new project, the researchers followed up on the fact that OGT interacts with important proteins called TET enzymes, discovered by the Rao Lab in 2009. TET proteins are part of the complex machinery that makes sure our DNA is correctly modified in our cells and that our cells activate the right transcriptional programs.

"TET proteins are involved in the critical cycle of DNA modifications, where they play a role in a process that results in the removal of molecular markers that attach to DNA (an event called DNA demethylation). The most abundant DNA markers, called 5mC and 5hmC, are normally associated with transcriptional silencing and activation, respectively. Researchers have shown that 5mC is associated with genes turned "off" while 5hmC, mediated by TET proteins, is associated with gene expression turned "on."

"This "on/off" epigenetic system gives our cells the flexibility to respond to environmental changes and health threats. DNA demethylation helps our immune cells spring into action if they detect a threat.

"DNA demethylation is normal, but cells also need balance. You can't have TET proteins activating every gene at the same time. In normal cells, TET protein activity is restricted to the genes that need to be expressed in that particular cell type.

***

"The researchers found that OGT protects cells by restraining TET activity. This is extremely important for controlling TE expression because it prevents the silencing modification 5mC from being converted to the activating modification 5hmC in heterochromatin.

"Without OGT at the helm, TET proteins ramp up DNA demethylation in the wrong places, turning on too many genes at once, including intact TEs normally "buried" in our genetic material.

"This finding shows how the non-coding regions of our genome can turn active when TET functions are altered. The new understanding of the OGT-TET partnership shows that these proteins, their mediated marks, and TE expression can affect our cells in a big way.

"'We think of these elements as totally 'silent,' and therefore completely inert, but the reality is that cells have to make a huge—and constant—investment to keep TEs silent," says Sepulveda.

Comment: another complex layer to genome activity, adding a more flexible set of responses. This is more evidence for design.

https://www.sciencedaily.com/releases/2025/03/250324113645.htm

"To prepare the 46 chromosomes of a human cell for transport to the daughter cells during cell division, each chromosome forms a compact X-shaped structure with two rod-like copies. How the cell achieves this feat remains largely unknown.

"Now, for the first time, EMBL scientists have directly observed this process in high resolution under the microscope using a new chromatin tracing method. The new study shows that the long DNA molecules of each chromosome form a series of overlapping loops during cell division that repel each other. As a result of this repulsion, the DNA loops then stack up to form rod-shaped chromosomes.

"Scientists have long hypothesised the importance of DNA loops in building and maintaining chromosomal structure. First identified in the 1990s, condensins are large protein complexes that bind DNA during cell division and extrude it to create loops of varying sizes. Previous studies from EMBL have shed light on the structural mechanics of this process and their essential role in packing chromosomes into forms that can be easily moved between cells.

"In fact, mutations in condensin structure can result in severe chromosome segregation defects and lead to cell death, cancer formation, or rare developmental disorders called 'condensinopathies'.

***

"...This technique, called LoopTrace, helped the researchers directly observe DNA in dividing cells as it progressively formed loops and folds.

"'Andreas and I were now able to visualise the structure of chromosomes as they started to change shape," said Beckwith. "This was crucial for understanding how the DNA was folded by the condensin complexes."

"From their data, the scientists realised that during cell division, DNA forms loops in two stages. First, it forms stable large loops, which then subdivide into smaller, short-lived nested loops, increasing the compaction at each stage. Two types of condensin protein complexes enable this process.

"...First, as observed, DNA forms overlapping loops -- first large and then small -- across its length with the help of Condensins. Second, these loops repel each other due to their structure and the chemistry of DNA. When the scientists fed these two assumptions into their model, they found that this was sufficient to give rise to a rod-shaped chromosome structure.

"'We realised that these condensin-driven loops are much larger than previously thought, and that it was very important that the large loops overlap to a significant extent," said Beckwith. "Only these features allowed us to recapitulate the native structure of mitotic chromosomes in our model and understand how they can be segregated during cell division."

***

"In the meantime, a second study from the Ellenberg Team, led by Andreas Brunner and recently published in the Journal of Cell Biology, shows that the nested loop mechanism is fundamental to the biology of cells, and continues during the cell's growth phase with another family of DNA loop forming protein complexes, called cohesins.

"'We were surprised to find that the same core principle of sequential and hierarchical DNA loop formation is used to either tightly pack chromosomes during division into safely movable entities, or to unpack them afterwards to read out the information they contain," said Ellenberg. "In the end, small, but key mechanistic differences, such as the non-overlapping nature of cohesin-driven loops compared to the strongly overlapping condensin-driven loops might be sufficient to explain the vast differences that we see in the shape the genome takes in interphase and mitosis under the microscope.'"

Comment: this very precise packing process had to be designed. I'm surprised that the role of histones as spools for the DNA is not mentioned.

https://www.livescience.com/health/genetics/speech-gene-seen-only-in-modern-humans-may-...

"A specific gene variant seen in people is likely one of many that contributed to the development of language in modern humans, scientists say. And it changes how mice squeak.

"Scientists have identified a gene that may have played a role in the emergence of spoken language in modern humans, or Homo sapiens.

"The gene, called NOVA1, carries instructions for a protein that plays a crucial role in brain development by binding to and regulating genetic material called RNA in neurons. Among other functions, RNA acts as an intermediary to relay blueprints from the genome to protein-construction sites inside cells. Although other mammals also have the NOVA1 gene, modern humans carry a special version in which one building block of the resulting protein is swapped with another. Specifically, a compound called isoleucine is replaced with valine.

***

"...the researchers found that the human version of NOVA1 seemed to change the frequency, pitch and musicality of squeaks made by baby mice. The human gene variant also influenced the melody and articulation of mating calls made by adult male mice to female mice, compared with the "typical" calls made by unmodified mice. (The modified mice did not start speaking like tiny humans at any point.)

"Taken together, these findings provide further evidence for the role of NOVA1 in vocalization. But what could this tell us about how spoken language first appeared in H. sapiens?

"To answer this question, the researchers analyzed eight genomes from living people as well as four genomes from our ancient human relatives, the Neanderthals and Denisovans. It turns out that neither of those relatives carried the same version of NOVA1 that we do, confirming earlier research conducted by other scientists.

"This finding suggests that the building-block swap in NOVA1 may have benefited H. sapiens by somehow enabling spoken language, and therefore, the trait would have been selected for over evolutionary time because it aided survival. As such, it increased in frequency within the population. Indeed, in the same study, the researchers looked at 650,000 modern human genomes in a database and found that all but six carried the human NOVA1 variant.

"Despite these findings, the researchers cautioned against concluding that they've identified a single "human language gene." It's likely that, in addition to NOVA1, other genes helped modern humans begin speaking.

***

"'We think it's hard science that NOVA[1] has an entirely human-specific variant that no other species we know of ever had," Darnell said, "and we can correlate that variant with changes in vocalization and language." Nonetheless, there are likely many genes, including FOXP2, that may be involved in language development in modern humans, he added."

Comment: it is not surprising we have or own language gene.

https://www.the-scientist.com/ribosomes-team-up-to-translate-tricky-mrna-segments-72543

"During translation, multiple ribosomes travel along the nucleic acid chain to build polypeptides that become functional proteins. Occasionally, these molecular decoders pause on the mRNA, either because they are instructed to do so or they have difficulty traversing the sequence. Previous studies that investigated these events looked at isolated ribosomal proteins as opposed to the multiple ribosomes typically involved in translation, leaving questions about how these pauses affect translation and how they are overcome.

"To elucidate this process, a team led by Marvin Tanenbaum, a molecular biologist studying single-molecule dynamics at Hubrecht Institute, developed a novel imaging method to study ribosome dynamics. In a study published in Cell, Tanenbaum and his team demonstrated that ribosomes use collisions to move past pause sites and other complicated segments of mRNA to increase translation efficiency.2 These findings introduce a new mechanism in translation and polypeptide formation.

***

"As Tanenbaum and his team watched translation unfold, they found that at any given time, each socRNA was bound by one to four ribosomes and that these molecular machines exhibited varied translation speeds. With the help of computational models, the researchers demonstrated how faster incoming ribosomes “bump into” the stalled-out ribosomes. These collisions occurred rapidly even when there were as few as two ribosomes on the socRNA.

***

"Since these brief collisions did not induce translation termination and ribosome disassembly, the researchers explored other ways that these encounters influenced ribosome activity. They found that when a sequence included a pause site, translation occurred faster if there were two ribosomes translating the socRNA compared to just one. This effect, which they termed ribosome cooperativity, extended to delays in other difficult mRNA regions, such as translation through repetitive sequences and complicated RNA structures.

“'This allows ribosomes to endure short collisions on problematic RNA sections, thereby promoting continuous protein production”, Maximilian Madern, a PhD student in Tanenbaum’s group at Hubrecht Institute and study coauthor, said in a statement.

"Lastly, the team evaluated the effect of ribosome cooperativity on socRNA sequences that did not include specific pause sequences or problematic patterns. Whereas translation with a single ribosome led to extended pauses in about five percent of the translation runs, sequences translated with two or more ribosomes experienced reduced pausing.

"These findings support a new mechanism in maintaining translation efficiency and help elucidate the process of ribosome recycling."

Comment: a mechanism as simple as pushing along helps in the translation work. Not everything is highly complex.

https://www.livescience.com/health/genetics/scientists-just-rewrote-our-understanding-o...

"Now, in a study published Jan. 17 in the journal Cell, scientists have uncovered a whole new method of gene regulation that involves epigenetic tweaks made to both DNA and its molecular cousin RNA, at the same time.

***

"In recent years, researchers have also found that RNA — a molecule that shuttles instructions from DNA out into the cell to make proteins — can also be modified. This is mainly done by a protein complex called METTL3-METTL14. This methylation can destabilize the RNA molecule, reducing the amount of protein made.

"Every cell in the body uses both RNA and DNA methylation to regulate gene expression. However, it was previously assumed that these processes operated independently. The new study puts that assumption into question.

"In the study, the scientists looked at mouse embryonic stem cells and mapped the locations of DNA and RNA methylation as the cells developed. They found that thousands of genes and their complementary RNA molecules contained both methylation markers.

"Through additional experiments, the team found that the METTL3-METTL14 complex that interacts with RNA also recruits and physically binds to DNMT1, the protein that tags DNA. This new, bigger complex can then methylate the same gene at the DNA or RNA level. This enables the cell to further fine-tune its gene regulation during cell differentiation — a process by which a stem cell assumes a specific identity, becoming a heart or lung cell, for example.

"Previous studies have shown clear connections between DNA and histone modifications, as well as between histone and RNA modifications.

***

"[Our study shows] the direct connection between DNA methylation and RNA modification that has not been seen before," he told Live Science.

"According to Fuks, this study does have some limitations, namely, that it mostly focuses on embryonic stem cell differentiation. DNA and RNA modifications had separately been well characterized in stem cells in past studies, so it made sense for the researchers to start with them. But these same types of DNA and RNA modifications are present in all types of cells.

"'Seeing this, it's very unlikely that [this mechanism] will be just in ES cells," Fuks said.

***

"If the coordination of DNA and RNA epigenetics gets thrown off, you may end up with too much or too little of a protein, Fuk suggested. "Now, a key protein will be expressed at a too high level," he said."This could be detrimental for a cell and contribute to tumorigenesis," or the formation of tumors."

Comment: this is a logical discovery from a design standpoint. DNA and RNA need to work hand- in-hand to fine-tune protein production levels to exact amounts.

https://www.sciencedaily.com/releases/2025/02/250207122612.htm

"A complex molecular machine, the spliceosome, ensures that the genetic information from the genome, after being transcribed into mRNA precursors, is correctly assembled into mature mRNA. Splicing is a basic requirement for producing proteins that fulfill an organism's vital functions. Researchers have succeeded for the first time in depicting a faultily 'blocked' spliceosome at high resolution and reconstructing how it is recognized and eliminated in the cell.

***

"The genetic information of all living organisms is contained in the DNA, with the majority of genes in higher organisms being structured in a mosaic-like manner. So the cells are able to "read" the instructions for building proteins stored in these genetic mosaic particles, they are first copied into precursors of mRNA, or messenger RNA. The spliceosome then converts them into mature, functional mRNA. To do this, this large protein-RNA complex, which is located in the cell nucleus, removes non-coding sections (introns) from mRNA precursors and links the coding sections (exons) to form a continuous strand of information. Errors in this process, also known as splicing, are one of the main causes of inheritable genetic disorders and are associated with neurodevelopmental disorders and diseases such as cancer. It was known that the spliceosome has quality control mechanisms, but the mechanistic details were not understood.

***

"Based on this structural information, the scientists were able to understand which errors occur during splicing, how the spliceosome recognizes faulty processes and subsequently aborts the splicing, thereby sorting out the faulty complex. Using the detailed structures, the researchers were also able to model the underlying molecular mechanisms. The proteins involved in this process of cellular quality control are conserved in eukaryotic organisms from fission yeast to humans. The scientists therefore assume that the mechanisms for recognizing and sorting out faulty spliceosomes have remained largely unchanged over the course of evolution."

Comment: more evidence for design. Something this complex cannot appear by chance mutations.

https://phys.org/news/2025-02-repressed-ready-bivalency-developmental-genes.html

"As well as being essential in the precise packaging of DNA into the space of the nucleus, histone proteins are also the site of modifications, chemical additions referred to as epigenetic marks, that control whether a gene is silenced or expressed.

"A specialized version of this control is at sites where both activating and repressive marks are laid down, called bivalency.

***

"The combination of active and repressive marks is thought to hold the gene in a poised state in undifferentiated cells, ready for either full activation or full and permanent repression depending on differentiation cues.

"Now the team's research has shown in part how this balance is achieved and identified the protein interactors that read the bivalent state and influence gene expression.

"Dr. Devisree Valsakumar, a postdoctoral researcher in the Voigt lab, explained, "Bivalent marks are the gatekeeper of the poised status, which we can compare to the 'Set' command of 'Ready, Set, Go!' As the later findings of our research showed, this regulation, which holds genes in a 'ready to go' state, is critical for the proper specialism of cell types as cells differentiate from stem cells."

"Key to identifying the readers of bivalency was the team's ability to create specifically modified histones and nucleosomes (where DNA is wound around histone proteins in a "beads on a string" structure). Through painstakingly recreating the DNA and histone protein complexes to allow tailored protein interaction assays, the team has shown that at bivalent locations, proteins were recruited to the repressive mark (H3K27me3) and not to the activating mark (H3K4me3).

"Importantly, the researchers discovered that the bivalent combination of activating and repressive marks allows the binding of specific proteins that are not recruited by the repressive (H3K27me3) or activating (H3K4me3) marks individually.

"One of these proteins is the histone acetyltransferase complex KAT6B (MORF), identifying this for the first time as a reader of bivalent nucleosomes and regulator of bivalent gene expression during embryonic stem cell (ESC) differentiation.

"When KAT6B was knocked out in embryonic stem cells, the cells showed diminished differentiation potential to form neurons when compared to unaltered controls. The team showed that this was caused by a failure to properly regulate the expression of bivalent genes, indicating that KAT6B contributes to the poised state of bivalent genes, ensuring their proper activation during ESC differentiation.

"Dr. Philipp Voigt, a tenure-track group leader in the Institute's Epigenetics research program, commented, "Our research provides insight into a long-standing paradigm in the regulation of developmental gene expression, revealing a key mechanism that has so far eluded experimental scrutiny.

"'It also uncovers a new layer of histone-based regulation, suggesting that bivalency is much more complex than originally thought. We are excited to now figure out what additional layers of regulation exist and how these contribute to poising and the control of developmental gene expression."

Comment: another excellent example of design. When to activate a gene depends upon a multiplicity of factors and requires very active controls.

https://www.the-scientist.com/ribosomes-team-up-to-translate-tricky-mrna-segments-72543...

"In a study published in Cell, Tanenbaum and his team demonstrated that ribosomes use collisions to move past pause sites and other complicated segments of mRNA to increase translation efficiency.2 These findings introduce a new mechanism in translation and polypeptide formation.

***

"As Tanenbaum and his team watched translation unfold, they found that at any given time, each socRNA was bound by one to four ribosomes and that these molecular machines exhibited varied translation speeds. With the help of computational models, the researchers demonstrated how faster incoming ribosomes “bump into” the stalled-out ribosomes. These collisions occurred rapidly even when there were as few as two ribosomes on the socRNA.

***

"Since these brief collisions did not induce translation termination and ribosome disassembly, the researchers explored other ways that these encounters influenced ribosome activity. They found that when a sequence included a pause site, translation occurred faster if there were two ribosomes translating the socRNA compared to just one. This effect, which they termed ribosome cooperativity, extended to delays in other difficult mRNA regions, such as translation through repetitive sequences and complicated RNA structures.

“'This allows ribosomes to endure short collisions on problematic RNA sections, thereby promoting continuous protein production”, Maximilian Madern, a PhD student in Tanenbaum’s group at Hubrecht Institute and study coauthor, said in a statement.

"Lastly, the team evaluated the effect of ribosome cooperativity on socRNA sequences that did not include specific pause sequences or problematic patterns. Whereas translation with a single ribosome led to extended pauses in about five percent of the translation runs, sequences translated with two or more ribosomes experienced reduced pausing.

Comment: more complexity in the translation mechanism. Mechanical forces play a large role. An obvious clue supporting design theory.

https://www.science.org/content/article/dark-proteome-survey-reveals-thousands-new-huma...

"...recent tallies have moved even lower, to about 20,000. But a new systematic analysis of what some call the “dark proteome” suggests scientists have missed thousands of nontraditional genes that lurk in previously overlooked stretches of the genome and make smaller than average proteins.

"The newly described genes and their products could upend aspects of human biology and accelerate medical discoveries. For example, one newfound gene makes a miniature protein that appears key to a childhood cancer.

***

"He and his colleagues expanded the standard definition of a gene, typically assumed to consist of a long protein-coding DNA sequence known as an open reading frame (ORF), which has signals telling a cell where to start and stop reading it. A cell transcribes the ORF sequence into messenger RNA, which travels to cellular factories called ribosomes that assemble amino acid sequences into proteins. A typical ORF is also preceded by a snippet of DNA that attracts the proteins needed for the gene to be read. And for most researchers, an ORF qualified as a gene if it encoded a protein with 100 or more amino acids.

"But biologists studying everything from yeast to snakes to humans have recently unearthed a plethora of so-called noncanonical ORFs, which lack those prefatory snippets and are shorter than average. Yet they are often transcribed into RNA, and a method known as ribosomal profiling, or Ribo-Seq, has shown that many of the transcribed RNAs attach to ribosomes, where they may be translated into short amino acid chains—even proteins with less than a dozen amino acids.

***

"So they teamed up with gene annotation specialist Jonathan Mudge of GENCODE, the database of officially recognized genes, and ultimately recruited several dozen other researchers from 20 institutions across four continents to help assess how many human noncanonical ORFs exist.

***

"By 2022, the scientists had tracked down 7264 noncanonical ORFs in the human genome. With the help of the Human Proteome Organization, which seeks to catalog all human proteins, and PeptideAtlas, which compiles mass spectrometry data on proteins, they set out to show that these ORFs make proteins.

"That was a “big challenge,” Youn notes. The consortium scoured PeptideAtlas’s archive of mass spectrometry data for small proteins that matched ORF sequences and sorted through published experiments that cataloged protein fragments detected by the human immune system, a blossoming field called immunopeptidomics. All told, they confirmed that one-quarter of the 7264 noncanonical ORFs they had tallied made proteins, some 3000 in all. (An ORF can be read multiple ways to make more than one protein.)

***

"They also give scientists new biomedical targets for study. Prensner and van Heesch had already begun to follow up on an ORF and its miniprotein they identified early in their dark proteome studies. By using the gene editor CRISPR to introduce mutations in the ORF, they could examine its protein’s importance in cancer cells. Though small, the ORF’s product is essential for the survival of medulloblastoma tumors, a brain cancer that affects children,

***

"Although Martinez is pleased with how much of the dark proteome has been uncovered, Youn believes much more remains to be found. The work her team and others have done casts just “slivers of light,” she says, on an unseen population of miniproteins. Her team is refining mass spectrometry techniques to detect ever smaller molecules and hopes to use them to find miniproteins that play a role in brain development.

"Where does all this leave the tally of human genes? The dark proteome has clearly boosted the total, but no one knows the true number.

“'My gut feeling it is probably not as high as 100,000,” Martinez says, “but 50,000 is in the realm of possibility.'”

Comment: it is obvious we are too complicated for just 20,000 genes. This research looks like they have found the answer in ORF's.

https://phys.org/news/2024-11-gene-results-extensive-regions-dna.html

"Some sequences in the genome cause genes to be switched on or off. Until now, each of these gene switches, or so-called enhancers, was thought to have its own place on the DNA. Different enhancers are therefore separated from each other, even if they control the same gene, and switch it on in different parts of the body.

"A recent study from the University of Bonn and the LMU Munich challenges this idea. The findings are also important because gene switches are thought to play a central role in evolution. The study has been published in the journal Science Advances.

"The blueprint of plant and animal forms is encoded in their DNA. But only a small part of the genome—about two percent in mammals—contains genes, the instructions for making proteins. The rest largely controls when and where these genes are active: how many of their transcripts are produced, and thus how many proteins are made from these transcripts.

"Some of these regulatory sequences, called "enhancers," work like dimmer switches used to modulate the light in our living room. Indeed, they specifically increase the expression of a particular gene, where and when this gene is required. Genes controlling morphology often respond to several independent enhancers, each determining the expression of the gene in a different body part.

***

"'We have taken a closer look at two of these enhancers," says Museridze.

"The first controls the formation of a color pattern on the wings, while the second controls the coloring of the head, thorax and abdomen. Both are active at the same time during the fly's metamorphosis. The team discovered that the body enhancer is not, as expected, located in a different region of DNA from the wing enhancer.

"Instead, there are extensive regions of DNA that belong to both gene switches, i.e. they influence the pigmentation of both the wing and the body.

"The results suggest that the architecture of regulatory sequences in the genome is much more complex than previously thought. This has far-reaching implications for how traits change during evolution. According to current knowledge, enhancers play a key role in this process.

"This is because many proteins are so important to an organism that a mutation in their gene (i.e., the DNA sequence that contains the instructions for building the protein) would cause serious problems or even certain death. As a result, genes that control body shape, such as the number of wings or legs, rarely change over the course of evolution. Enhancers offer a way out of this dilemma: when they mutate, the activity of the corresponding gene changes, but only in a specific tissue and at a specific time.

"'The cost of mutating an enhancer is therefore often lower than the cost of mutating the gene directly," says Mariam Museridze.

"This makes it easier for new traits to emerge during evolution. It is like baking a cake: If you mix eggs, flour, milk and sugar, you can get completely different types of dough, depending on the mixing ratio. In this metaphor, the enhancers would be responsible for the quantity of ingredients, not the type of ingredients.

"A genetic mutation is like accidentally replacing one ingredient with something completely different—for example, using sawdust instead of flour. The result will certainly not taste very good. A mutation in an enhancer, on the other hand, would change the amount of flour.

"'If enhancers are not as modular as we thought, this means that mutations in them can have much broader effects," says Museridze.

"This means that such a mutation could affect the amount of several ingredients at the same time. However, it is also possible that the enhancers retain their independence and continue to control the amount of a single ingredient, even though their sequences are interwoven and shared."

Comment: this is a clever way to control change, to modulate it through the enhancers. A mutation can have a variety of effects,

https://www.the-scientist.com/how-stem-cells-stay-young-72321

"Aging is inevitable for most cell types in the human body, but hematopoietic stem cells (HSCs) seem to defy the process. They retain their self-renewing ability almost throughout an organism’s lifetime and exhibit a delayed onset of typical hallmarks of aging like DNA damage or protein aggregation. “Stem cells are really remarkable in their longevity,” said Andre Catic, a researcher working on aging at the Baylor College of Medicine.

"Previously, scientists found that one reason contributing to HSC longevity was that they could exist in a functionally inactive state for prolonged periods.1 Now, Catic and his team found another clue as to how these cells maintain their youth. In a study published recently in Nature Cell Biology, they reported that HSCs contain high levels of a protein cyclophilin A which prevents these cells from rapid aging.2 Understanding mechanisms of how HSCs avoid the wear and tear of senescence has wide-ranging implications, from figuring out cells’ fundamental anti-aging secrets to determining how these mechanisms breaking down could lead to leukemia.

***

"Curious as to why that’s the case, Catic and his team isolated stem and progenitor cells from the bone marrow of mice to see if there was something in their proteome. As aging in other cells is driven by proteins clumping together, they combed the proteome for mechanisms that could cause less protein aggregation or clear up existing protein clumps.

"That’s how they came across cyclophilin A, a chaperone that was highly expressed in these HSCs. The scientists found that aged HSCs had lower levels of cyclophilin A, and that genetically removing it from young HSCs accelerated their aging. They also showed that re-introducing cyclophilin A to older HSCs rejuvenated them and improved their functions. All the evidence pointed towards this chaperone playing a key role in the longevity of these stem cells.

“'What is interesting is that it's not one of those chaperones that is active at the back end of proteins’ lives,” said Catic. “Many chaperones, they help misfolded proteins, [they] refold them again, and get them back into solution, or they're involved in their degradation. Cyclophilin A is involved in the first step of protein synthesis.”

"Next, the team further investigated cyclophilin A to better understand its role in translation. When they checked what kinds of proteins it bound to, they found many RNA-binding proteins involved in ribosome assembly. Based on their findings, the scientists hypothesized that cyclophilin A was associated with ribosomes and inferred that it could be helping proteins fold as they come out of the ribosome.

"The team also found that this chaperone aided the synthesis of proteins filled with intrinsically disordered regions (IDRs). These indetermined structures within the proteins are also called floppy domains. As they don’t have a very fixed structure, such proteins can adopt whatever conformation is needed, according to Catic.

"An advantage of this flexibility is that these proteins can have multiple binding partners; they can act as scaffolding proteins that can bring together other proteins, RNA, and DNA to form complexes in the cell. “They help entire pathways come together, and that is why we believe they're important for so many basic processes such as splicing and translation,” said Catic.

"Catic believes that these intrinsically disordered proteins could be involved in many important cellular functions which help keep the stem cells healthy, which is why cyclophilin A promoting their translation is helpful for the stem cells’ longevity."

Comment: careful research has shown how these stem cells survive. How did this evolve? Not by chance. How does chance know in advance how long animals might live and need new blood cells? Obvoiusly it doesn't. Only chance can create this.

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/25_october_2024/422...

"Guided by its predictions, both have independently identified a complex of three proteins that sits on the head of a sperm and locks onto the surface of an egg cell during fertilization.

***

"In 2005, a team in Japan showed that deleting a particular gene in mice caused the animals to make healthy looking, motile sperm that nevertheless failed to fuse with egg cells. They named the gene Izumo1, after a Shinto shrine to marriage. Nearly a decade later, another group discovered a protein receptor on egg cells that bound to Izumo1, and named it Juno, after the Roman goddess of fertility. Others have found additional proteins: In 2020, for example, a team showed mice that had had their Spaca6 gene knocked out produced sperm with the same defects as rodents lacking Izumo1.

***

"In both teams’ studies, the AI program predicted the formation of a three-protein complex, or trimer, on sperm between Izumo1, Spaca6, and another known protein, Tmem81, which had not previously been associated with fertilization. In the eLife study, the team including Wright and led by structural biologist Luca Jovine at the Karolinska Institute analyzed mouse and human protein structures with the program and found the trimer could form a larger complex with Juno and another protein on egg cells called CD9.

"The other team, led by molecular biologist Andrea Pauli at the Research Institute of Molecular Pathology (IMP) at the Vienna Biocenter, went further and carried out experiments to see whether their AI-identified complex existed in the real world. They found that deleting the gene for Tmem81 in zebrafish and mice caused the same sperm defects as did deletions of Izumo1 or Spaca6, confirming this third protein was also critical for fertilization.

"The researchers also found that adding antibodies for Izumo1, Spaca6, or Tmem81 to samples of zebrafish sperm always pulled out all three proteins together, confirming they formed a trimer, as AI had predicted. “I think that was probably one of the happiest days in lab,” says Victoria Deneke, an IMP molecular biologist and co-author of the Cell paper. “It’s not a prediction … it’s actual experimental data.”

"Surprisingly, AlphaFold-Multimer also predicted—and experiments with zebrafish proteins subsequently supported— that different parts of this sperm trimer are responsible for binding to the distinctive receptors of mammalian versus zebrafish eggs. It’s remarkable that the sperm complex has stayed the same across vertebrate evolution whereas egg receptors have changed, Pauli says. The findings might reflect how eggs adapted to different environments—fish eggs are typically fertilized outside the animal, whereas mammalian eggs are fertilized within."

Comment: A complex of three proteins must be found by chance or the process is designed. Logically it is designed. especially considering the necesary eggv receptors.

https://www.the-scientist.com/ovarian-proteins-that-last-a-lifetime-help-maintain-egg-c...

"In a recent study, Schuh and her team showed that cells in the mammalian ovary contain proteins with extremely long lives.1 The findings, published in Nature Cell Biology, shed light on the adaptations that help maintain oocytes with minimal damage throughout a female animal’s reproductive life and offer clues about fertility decline in aging ovaries.

“'Although the biology of extremely long-lived proteins in aging has been known for a while, this is the first paper to carefully characterize the nature and identity of those proteins in the ovary,” said Lei Lei, a reproductive biologist at the University of Missouri School of Medicine, who was not associated with the study. Making new proteins comes with the risk of making mistakes, which oocytes cannot afford to do, she added. “Because after all, you’re going to support a new life.”

***

"The long-lived proteins belonged to different cell components like mitochondria, ribosomes, and chromatin, and were involved in functions like metabolism and DNA repair.

"The ovary consists of cells other than oocytes, like stromal and thecal cells, that play essential roles in fertility. The team wondered whether these cells also housed long-lived proteins. They analyzed proteins from the ovaries of mice up to 15 months old, an advanced age for mice. Mathematical modeling showed that more than 10 percent of the proteins had a half-life of more than 100 days, with many persisting in the ovaries for most of the animals’ lives. In comparison, less than one percent of proteins in the cartilage, brain, and muscle had such long lives. These long-lived ovarian proteins have essential functions in structures like the mitochondria and cytoskeleton, and processes like protein homeostasis and chromatin maintenance. RNA sequencing revealed that aside from oocytes, a subset of somatic cells in the ovary also carried such long-lived proteins.

"The researchers next wondered how these proteins were able to persist for such a long time. To determine if altered protein homeostasis played a role, they tested whether aged oocytes contained aggregates of misfolded proteins. Microscopy revealed no such aggregates in aged oocytes. The researchers further confirmed that age did not reduce the activity of proteasomes—complexes that degrade misfolded proteins to maintain protein homeostasis in cells.

"Analyzing protein abundance in the ovaries showed enrichment of antioxidants and chaperones that help in protein folding, suggesting that proteins are maintained over long periods by preventing protein misfolding and protecting against oxidative damage.

***

"Mass spectrometry revealed that ovarian aging is associated with a reduction of many long-lived proteins. This causes an extensive remodeling of the ovarian protein landscape, which eventually leads to gradual fertility decline after the age of three months in mice.

"Finding long-lived proteins in the ovary was not entirely unexpected, said Schuh. “But that so many proteins persist for a very long time period, that was surprising,” she said. Her team has started looking into some of these long-lived proteins to understand why they do not degrade more often, and what the functional implications of their longevity are.

***

“'How [these results] relate directly to humans, we do not know yet,” agreed Schuh. However, she expects that human ovarian proteins would also be long-lived. Although it’s difficult to study this in people at the moment, she noted that, “expanding this to humans one day would be absolutely exciting.'”

Comment: this arrangement requires conceptual thought. It must be recognized that repeated copying results in errors. Darwin style evolution can't do that. Design can.

https://www.the-scientist.com/dna-polymerase-works-in-short-bursts-rather-than-one-long...

"...suggesting that DNA replication and proofreading involves multiple polymerases. Now, in a publication in Nature Communications, a team at Vrije University Amsterdam provided additional evidence that DNA polymerase does not replicate DNA as continuously as once believed.

***

"The researchers observed that, on average, a single DNA polymerase molecule remained bound to the nucleic acid at the junction for slightly more than one second—far from the continuous binding that most textbooks describe. Further contrasting from the dogma, during this time, a single enzyme only performed either extension or proofreading, occasionally also pausing on the DNA; rather than backing up to fix an error, the enzyme detached from the nucleic acid to let another bind.

“'The idea of having a motor that you put in reverse sounds very appealing to us, but it's much more efficient to throw the motor out,” Wuite explained. Unlike cars, a cell has multiple DNA polymerase motors, so an enzyme that is already in the configuration needed to bind the DNA and correct the error can take over. This exchange takes less energy than the same protein changing conformation to fulfill a different function.

"However, DNA polymerase’s activity appeared seamless and uniform, so the team considered that a process existed to help one enzyme pick up where another left off, acting like a memory. They analyzed one extension event and observed that polymerases unbound and rebound multiple times, but each time, they resumed the same function.

"To study this further, the team assessed the activity state—enzymatic or paused—before, during, and after a fluorescent polymerase bound the DNA over the course of several experiments. They found that the most common pattern was for the activity to be the same at all three observational points, whether the enzymatic period was during exonuclease repair or DNA extension.

“'This experiment is really the nail in the coffin of this model where everything is sitting stably on the DNA,” van Oijen said. He added that structural studies will be important for adding additional context to these mechanisms."

Comment: this adds much more complexity to the process of DNA copying with many more moving parts. Recognizing mistakes means the molecules carry a copy of what is expected as they read the new copy. As all of this is highly repetitive and exacting only design could produce it.

https://www.sciencedaily.com/releases/2024/10/241004121853.htm

"DNA damage response, or DDR for short, is the technical term for this. Specific signaling pathways usually initiate the immediate recognition and repair of DNA damage, thus ensuring the survival of the cell.

***

"The group has identified a new mechanism of the DNA damage response that is mediated via an RNA transcript. Their results help to broaden the conceptual view on the DNA damage response and to link it more closely with RNA metabolism.

***

"'In our study, we focused on so-called long non-coding RNA transcripts. Previous data suggest that some of these transcripts act as regulators of genome stability," says Kaspar Burger, explaining the background to the work. The study focused on the nuclear enriched abundant transcript 1 -- also known as NEAT1 -- which is found in high concentrations in many tumor cells. NEAT1 is also known to react to DNA damage and to cellular stress. However, its exact role in the DNA damage response was previously unclear.

"'Our hypothesis was that RNA metabolism involves NEAT1 in the DNA damage response in order to ensure the stability of the genome," says Burger. To test this hypothesis, the research group experimentally investigated how NEAT1 reacts to serious damage to the genome -- so-called DNA double-strand breaks -- in human bone cancer cells. The result: "We were able to show that DNA double-strand breaks increase both the number of NEAT1 transcripts and the amount of N6-methyladenosine marks on NEAT1," says the scientist.

***

"The experiments conducted by Kaspar Burger and his team show that the frequent occurrence of DNA double-strand breaks causes excessive methylation of NEAT1, which leads to changes in the NEAT1 secondary structure. As a result, highly methylated NEAT1 accumulates at some of these lesions to drive the recognition of broken DNA. In turn, experimentally induced suppression of NEAT1 levels delayed the DNA damage response, resulting in increased amounts of DNA damage.

"NEAT1 itself does not repair DNA damage. However, as the Würzburg team discovered, it enables the controlled release and activation of an RNA-binding DNA repair factor. In this way, the cell can recognize and repair DNA damage highly efficiently."

Comment: another very precise mechanism to aid in DNA repair. In separating chromosomes during cell splitting forces are acting and can cause tears. This is unlike a mistake in folding, thus another form of mistake as is the joining improperly of molecules. Living mistakes are or was the result of all these free-floating actions, upon which operational life begins.