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Lab captures invisible details of replication, suggests how mutations can occur – ScienceDaily

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When cells proliferate, the internal mechanisms that copy DNA cope almost every time. Bioscientists from Rice University have discovered a tiny detail that helps us understand how the process can go wrong.

Their study of enzymes showed that the presence of a central metal ion, important for DNA replication, is also relevant to the incorrect ordering of nucleotides on new chains.

Surveillance is reported in The nature of communication can help find treatments for genetic mutations and the diseases they cause, including cancer.

Structural biologist Rice Yang Gao, graduate student Caleb Chang and alumni Christy Lee Luo used time-resolved crystallography to analyze flexible enzymes called polymerase as they bend and twist to quickly assemble complete DNA chains from pools C, G, A and T. nucleotides.

All proteins involved in DNA replication rely on metal ions – magnesium or manganese – to catalyze the transfer of nucleotides to the proper places along the chain, but whether two or three ions have been involved has long been the subject of debate. .

Rice’s team seems to have solved this by studying polymerase, known as eta, a translation synthesis enzyme that protects against damage caused by ultraviolet light. According to researchers, people with mutations in the poly-eta gene often have a predisposition to xeroderma pigmentosum and skin cancer.

Gao said typical polymerases resemble the shape of a right hand, and he thinks of them in terms of a real hand: “They have a palm domain that contains the active site, a finger domain that closes to interact with a new base pair, and a thumb domain. which binds the DNA of the primer / template, ”he said.

But so far, scientists have only been able to guess at some of the details of the well-hidden mechanism by which polymerases do their job, and sometimes fail. The type of time-resolved crystallography used in the GAO lab has allowed researchers to analyze proteins crystallized in 34 intermediate stages to determine the position of their atoms before, during and after DNA synthesis.

“This kinetic response is hard to catch because there are a lot of atoms and they work very fast,” said Gao, an associate professor of biological sciences who joined Rice as a CPRIT scientist in 2019. “We never knew how atoms move together because spatial information was lacking. Freezing proteins and a small molecular substrate allows us to capture this catalytic reaction for the first time.”

The study led to their theory that the first of the three metal atoms in eta supports nucleotide binding, and the second is key to keeping nucleotides and primers in the way by stabilizing the binding of free nucleotides to a primer located on the existing half. new strand (aka substrate). Primers are short strands of DNA that mark the place where polymerases begin to string new nucleotides.

“Only when the first two metal ions are under control can the third come and cause a reaction at home,” Chang said, believing the process could be universal among polymerases.

The researchers also noted that the poly-eta contains a motif that makes it prone to primer incompatibility, leading to a greater likelihood of erroneous implementation.

“It’s, first of all, the basic mechanism of life,” Gao said. “DNA must be copied accurately, and mistakes can lead to human disease. People who study these enzymes know that for DNA synthesis they always do much, much better than they should because there is a very limited amount of energy available to choose from. the right base pair ”.

For GAO the real result is to prove the ability of crystallography with a time distribution to observe the whole catalytic process in atomic details.

“It allows us to see exactly what is happening in the dynamic catalytic process over time,” he said.

The study was supported by the Texas Institute for Cancer Prevention and Research (RR190046), the Welch Foundation (C-2033-20200401) and a doctoral fellowship from the Houston Molecular Biophysics Program (National Health Institute grant T32 GM008280).

Source of history:

Materials provided Rice University. The original was written by Mike Williams. Note: Content can be edited by style and length.

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