Genome complexity: cell division DNA controls (Introduction)

by David Turell , Sunday, July 02, 2023, 17:14 (300 days ago) @ David Turell

DNA has to be copied perfectly:

https://knowablemagazine.org/article/living-world/2023/how-dna-is-copied?utm_source=Kno...

"The cell controls the start of DNA replication in a two-step process. The whole goal of the process is to control the actions of a crucial enzyme — called a helicase — that unwinds the DNA double helix in preparation for copying it. In the first step, inactive helicases are loaded onto the DNA at the origins, where replication starts. During the second step, the helicases are activated, to unwind the DNA.

"Kicking off the process is a cluster of six proteins that sit down at the origins. Called ORC, this cluster is shaped like a double-layer ring with a handy notch that allows it to slide onto the DNA strands, Berger’s team has found.

"In baker’s yeast, which is a favorite for scientists studying DNA replication, these start sites are easy to spot: They have a specific, 11- to 17-letter core DNA sequence, rich in adenine and thymine chemical bases. Scientists have watched as ORC grabs onto the DNA and then slides along, scanning for the origin sequence until it finds the right spot.

"But in humans and other complex life forms, the start sites aren’t so clearly demarcated, and it’s not quite clear what makes the ORC settle down and grab on, says Alessandro Costa, a structural biologist...Replication seems more likely to start in places where the genome — normally tightly spooled around proteins called histones — has loosened up.

"Once ORC has settled onto the DNA, it attracts a second protein complex: one that includes the helicase that will eventually unwind the DNA. Costa and colleagues used electron microscopy to work out how ORC lures in first one helicase, and then another. The helicases are also ring-shaped, and each one opens up to wrap around the double-stranded DNA. Then the two helicases close up again, facing toward each other on the DNA strands, like two beads on a string.

***

"Things kick into high gear when a crucial molecule called CDK waves the green flag, jump-starting chemical steps that lure in even more proteins. One of them is DNA polymerase — what Costa calls the “typewriter” that will build new DNA strands — which hitches onto each helicase. Others activate the helicases, which can now burn energy to chug along the DNA.

"As this occurs, the helicases change shape, pushing on one DNA strand and pulling on the other. This creates strain on the weak hydrogen bonds that normally hold the two strands together by the bases — the As, Cs, Ts and Gs that make up the rungs of the DNA ladder. The two strands get ripped apart. Costa and colleagues have observed how the two helicases untwist the DNA between them, and they’ve seen how the helicases keep the unbound bases stable and out of the way.

"At first, both helicases are wrapped around both strands of DNA, and they can’t get very far like this, because they are facing each other and will just run into each other. But next, they each undergo a change in position, spitting one DNA strand or the other out of the ring. Now separated, they can jostle past each other, and replication proceeds apace.

"Each helicase motors along its single strand, in the opposite direction from the other. They leave the origin behind and yank apart those hydrogen-bonded base pairs as they travel. The DNA polymerase is right behind, copying the DNA letters as they’re freed from their partners.

"CDK’s second job is to stop any more helicases from hopping on the origins. Thus, there is one start of replication per origin, ensuring proper copying of the genome — although copying doesn’t begin at the same time at each site. The whole process of DNA replication, in human cells, takes about eight hours.

"There is still plenty to be worked out. For one thing, the DNA that’s being copied is not a naked double helix. It’s wrapped around histones and attached to lots of other proteins that are busy turning genes on or off or making RNA copies of the genes. How do those jostling proteins affect each other and avoid getting in each other’s way?"

Comment: This happens trillions of times a day. The rare mistakes add up over time to give the false impression that mistakes are common. This process, with all its parts acting in concert, is irreducibly complex and must be designed all at once.