Genome complexity: editing DNA and other controls (Introduction)

by David Turell , Thursday, April 02, 2020, 05:36 (1485 days ago) @ David Turell

Mutations can be good or bad and editing is very important:

https://evolutionnews.org/2020/03/more-hints-of-order-in-the-genome/

"... biochemists are finding that the differences in spelling are not just background noise; they alter the protein’s folding. Is that good or bad?

“'Synonymous mutations were long considered to be genomic background noise, but we found they do indeed lead to altered protein folding, and in turn impair cell function,” said Patricia Clark, the Rev. John Cardinal O’Hara professor of biochemistry. “Our results show that synonymous variations in our DNA sequences — which account for most of our genetic variation — can have a significant impact on shaping the fitness level of cellular proteins.”

"Surely many of these mutations are harmful, as are random mutations in humans that cause genetic disease. But E. coli has been around for a long time. Wouldn’t the species have gone extinct by now with the accumulation of defective spellings if they are always deleterious? Other work has suggested a “secret code” in synonymous variations that fine-tunes expression rates or regulates the supply of a given protein based on environmental conditions:

"Synonymous codon substitutions alter the mRNA coding sequence but preserve the encoded amino acid sequence. For this reason, these substitutions were historically considered to be phenotypically silent and often disregarded; it has become clear that synonymous substitutions can significantly alter protein function in vivo through a wide variety of mechanisms that can change protein level, translational accuracy, secretion efficiency, the final folded structure and posttranslational modifications.

***

"Bulock et al., have found one duplication enzyme that proofreads itself while proofreading its partner! “DNA polymerase δ proofreads errors made by DNA polymerase ε,” the paper is titled.

"Polδ and Polε are the two major replicative polymerases in eukaryotes, but their precise roles at the replication fork remain a subject of debate. A bulk of data supports a model where Polε and Polδ synthesize leading and lagging DNA strands, respectively. However, this model has been difficult to reconcile with the fact that mutations in Polδ have much stronger consequences for genome stability than equivalent mutations in Polε. We provide direct evidence for a long-entertained idea that Polδ can proofread errors made by Polε in addition to its own errors, thus, making a more prominent contribution to mutation avoidance.

"In other words, Polδ is a proofreader of a proofreader.

"Thus, the high efficiency of Polδ at correcting errors made by Polε may result from a combination of two factors: the high proclivity of Polε to yield to another polymerase and the greater flexibility and robustness of Polδ when associating with new primer termini.

***

"Researchers have explored further into the formation of this structure, which involves chromatin wrapping around histone proteins so that long strands of DNA can fit within the compact space of the cell nucleus. As with everything else in genomics, the structure doesn’t just happen. It requires a lot of help.

"Regulation of histone proteins allows the DNA strands become more tightly or loosely coiled during the processes of DNA replication and gene expression. However, problems may arise when histones clump together or when DNA strands intertwine...the misregulation of chromatin structures could result in aberrant gene expression and can ultimately lead to developmental disorders or cancers.

Histone chaperones are those proteins, responsible for adding and removing specific histones [found] at the wrong time and place during the DNA packaging process. Thus, they also play a key role in the assembly and disassembly of chromatin.

***

“'The fundamental unit of chromatin, the nucleosome, is an intricate structure that requires histone chaperones for assembly.” Their cryo-EM images of one particular chaperone named Abo1 reveals a six-fold symmetry with precise locations for docking to histones, its hexameric ring “thus creating a unique pocket where histones could bind” with energy from ATP. “Not only is Abo1 distinct as a histone chaperone,” they write, “but Abo1 is also unique compared to other canonical AAA+ protein structures.” Like Lego blocks, Abo1 features “tight knob-and-hole packing of individual subunits” plus linkers and other binding sites, such as for ATP.

"And unlike static blocks, these blocks undergo conformational changes as they work.

"Such sophistication is far beyond the old picture of DNA as a master molecule directing all the work. It couldn’t work without the help of many precision machines like this.

***

"Proteins must fold properly to perform their functions. Small proteins usually fold successfully on their own, but large ones can fall into several misfolding traps that are equally likely as the canonical fold. It appears that the “sequence of the sequence” in a gene has something to do with this. “Interestingly, many of these proteins’ sequences contain conserved rare codons that may slow down synthesis at this optimal window,” explain Amir Bitran et al. in a January 21 paper in PNAS, discovering that “Cotranslational folding” (i.e., folding that begins as the polypeptide exits the ribosome) “allows misfolding-prone proteins to circumvent deep kinetic traps.'”

Comment: Such complexity requires design. Nothing else can create this.