Accurate DNA Synthesis Across 8-Oxoadenine by Human PrimPol

TL;DR

Human PrimPol can accurately bypass DNA damage caused by 8-oxoadenine, a lesion from oxidative stress, using a specific mechanism.

Contribution

Demonstrates PrimPol's efficient and accurate translesion synthesis across 8-oxoadenine for the first time.

Findings

PrimPol accurately bypasses 8-oxoadenine with higher accuracy than 8-oxoguanine.

Mn2+ ions enhance PrimPol activity on DNA lesions via lesion skipping.

PrimPol efficiently handles multiple oxidative DNA lesions in nuclei and mitochondria.

Abstract

PrimPol is a human DNA primase and DNA polymerase involved in DNA damage tolerance in both nuclei and mitochondria. PrimPol restarts stalled replication forks by synthesizing DNA primers de novo and also possesses DNA translesion activity (TLS activity). PrimPol efficiently and relatively accurately bypasses several DNA lesions including 8-oxoguanine, thymine glycol and 5-formyluracil. In this work, we showed that PrimPol possesses efficient and accurate TLS activity across 8-oxoadenine, another common DNA lesion caused by oxidative stress. The accuracy of PrimPol on DNA with 8-oxoA was significantly higher compared to DNA containing 8-oxoG. Replacement of Mg2+ ions with Mn2+ stimulated activity of PrimPol on DNA with 8-oxoA and 8-oxoG as well as undamaged A in a sequence-dependent manner by the lesion skipping (or template scrunching) mechanism. Altogether, our data support the idea that PrimPol possesses efficient TLS activity across a wide range of DNA lesions caused by oxidative stress.

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