Genome complexity: 3-D DNA contortions ad complexity (Introduction)

by David Turell , Saturday, November 03, 2018, 18:01 (2213 days ago) @ David Turell

DNA just doesn't sit there. It is constant motion twisting and untwisting delivering genetic instructions:

https://www.quantamagazine.org/dna-supercoils-change-the-way-that-cells-work-20160105/

"DNA is probably best known for its iconic shape — the double helix that James Watson and Francis Crick first described more than 60 years ago. But the molecule rarely takes that form in living cells. Instead, double-helix DNA is further wrapped into complex shapes that can play a profound role in how it interacts with other molecules. “DNA is way more active in its own regulation than we thought,” said Lynn Zechiedrich, a biophysicist at Baylor College of Medicine and one of the researchers leading the study of so-called supercoiled DNA. “It’s not a passive [molecule] waiting to be latched on to by proteins.”

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"Zechiedrich’s work illustrates how DNA opens on its own. Simply twisting DNA can expose internal bases to the outside, without the aid of any proteins. Additional work by David Levens, a biologist at the National Cancer Institute, has shown that transcription itself contorts DNA in living human cells, tightening some parts of the coil and loosening it in others. That stress triggers changes in shape, most notably opening up the helix to be read.

:The research hints at an unstudied language of DNA topology that could direct a host of cellular processes. “It’s intriguing that DNA behaves this way, that topology matters in living organisms,” said Craig Benham.

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"Like the string, it prefers to be in its most relaxed state — the iconic double helix. But DNA rarely gets to relax. It’s subject to a continual onslaught of molecules that bind it — the enzymes that untangle, unwind and then replicate DNA; the molecules that mark which genes are active and which are silent; and the proteins that pack the lengthy molecule into a manageable size. All of these molecules contort DNA into new shapes, blocking it from the repose of the simple double helix.

"These interactions represent the inner workings of the cell, the basis of all life. How the cell decides to activate a certain gene, for example, involves a complex assembly of molecules in the right place at the right time.

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"Researchers have known since the 1970s that twisting DNA opposite the direction of the helix — called negative supercoiling — can split open the two strands. This split serves a dual purpose. It both relieves pent-up molecular stress and exposes the code hidden within the helix, granting access to the molecular machines that replicate DNA and make RNA.

"Levens and collaborators found that transcription twists DNA, leaving a trail of undercoiled (or negatively supercoiled) DNA in its wake. Moreover, they discovered that the DNA sequence itself effects how the molecule responds to supercoiling. For example, the researchers identified a specific sequence of DNA that’s prone to opening when stressed, like a weak spot in an old inner tube. The segment acts as a sort of chemical cruise control; as the amount of supercoil rises and falls, it slows or speeds the pace at which molecular machinery reads DNA.

"Levens says these structural changes also help DNA communicate along its length. Just as pressing an inner tube makes a weak spot bulge, changes in the shape of one part of the DNA molecule might trigger stress elsewhere along its length, which in turn might help regulate genes.

"The findings align with Harris’s models, which show that supercoiling can split the two strands of the helix, rotating the DNA bases that normally lie inside the helix to the outside, a phenomenon known as base flipping. Other simulations show that twisting a bit more flips out additional bases, creating a bubble of inside-out DNA. Zechiedrich theorizes these bubbles might provide trigger points for replication or gene expression. This challenges the standard view, in which proteins latch onto DNA and launch these events. “Who’s driving the bus in cellular metabolism?” said Sumners. “It’s a very dynamic process — DNA and proteins each influences how the other acts and reacts.'”

Comment: This 3-D dance in cells is constant as life maintains its balance or homeostasis. It has to be automatically making necessary choices or life's processes could be scrambled by imperfect reactions. Bit by bit we are unearthing the hidden layers of genome complexity, but there is one item we don't understand at all: we may know what gene controls what process or event, but we have no idea how it exerts its control. Finding the code for protein production was only a tiny step in understanding how complex the genome actually is.