May 9, 2014

Bypassing DNA damage

Studies of a human polymerase that replicates DNA have provided a complete kinetic and structural framework for understanding how the enzyme accurately bypasses DNA damage.

by Peng Xu


A number of factors, including oxidative stress, damage DNA and cause challenges during DNA replication. The most common oxidative “lesion” – 8-oxoG – is associated with cancer, aging, hepatitis and infertility. Among various mechanisms cells have for removing or bypassing lesions, Y-family polymerases bypass sites of damaged DNA in a less error-prone fashion.

In a “Paper of the Week” published online April 23 by the Journal of Biological Chemistry, Martin Egli, Ph.D., and colleagues used kinetic and mass-spectrometric studies to demonstrate that a member of the Y-polymerase family, human polymerase eta (hPol-eta), bypasses 8-oxoG in a largely error-free manner by preferentially incorporating dCTP (one of the DNA building blocks) opposite 8-oxoG.

Crystal structures of the native hPol-eta complex demonstrate that an arginine amino acid in the enzyme’s finger domain prevents formation of the more error-prone 8-oxoG:A pair. These novel findings provide a complete kinetic and structural framework for understanding how hPol-eta accurately bypasses the most common oxidative DNA lesion.

This research was supported by National Institutes of Health grants ES010375, CA160032 and ES000267.

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