The internal mechanisms that copy DNA get it right when cells reproduce. Rice University bioscientists discovered a tiny detail that helps understand how the process could go wrong.
The presence of a central metal ion critical to DNA replication appears to be implicated in misincorporation, the faulty ordering of nucleotides on new strands.
The observation reported in Nature Communications could help find treatments for genetic disorders.
Rice structural biologists and graduate students used time-resolved crystallography to analyze the polymerase as it bends and twists to quickly reassemble complete strands of DNA from a pool of C, G, A and T nucleotides.
The transfer of nucleotides to their proper positions along the strand depends on the metal ion used, but whether there were two or three involved has been a topic of debate.
The Rice team studied the eta, a translesion synthesis enzyme, which protects against ultraviolet-linked diseases. According to the researchers, people who have a poly-eta gene abnormality are more likely to get xeroderma pigmentosum and skin cancer.
He thinks of typical polymerases as a right-handed shape, with a palm domain that holds the active site, a finger domain that closes up to interact with the new base pair, and a thumb domain that binding.
Scientists have only been able to guess at some of the mechanisms by which the polymerases do their job. The type of time-resolved crystallography used in the lab allowed the researchers to determine the positions of the atoms before and after the synthesis of DNA.
There are many atoms and they work very fast, so it is difficult to capture this reaction. We can capture this reaction for the first time with the freezing of the proteins and small molecule.
The study led to the idea that the first of the three metal atoms in eta supports the binding of loose nucleotides to the primer located on the existing half of the new strand. Primers are short strands of DNA.
The process may be universal among polymerases if the first two metal ion are in check.
Poly-eta has a motif that makes it prone to misalignment of primers, which leads to a greater chance of misincorporation.
Errors can lead to human disease, and this is the first about a basic mechanism of life. People who study these synthesis enzymes know that they always do better than they should because there is a limited amount of energy available for them to choose the right base pair.
Time-resolved crystallography can be used to observe an entire catalytic process in atomic detail.
This allows us to see exactly what is happening in a dynamic catalytic process over time.
More information: Caleb Chang et al, In crystallo observation of three metal ion promoted DNA polymerase misincorporation, Nature Communications (2022). DOI: 10.1038/s41467-022-30005-3 Journal information: Nature Communications Citation: Crystal study may resolve DNA mystery (2022, May 9) retrieved 9 May 2022 from https://phys.org/news/2022-05-crystal-dna-mystery.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
All Rights Reserved © 2024
