TREX2 Deficiency Suppresses Spontaneous and Genotoxin-Associated Mutagenesis

Authors

Teresa Marple
Mi Young Son
Xiaodong Cheng
Jun Ho Ko
Patrick Sung
Paul Hasty

Publication Date

1-23-2024

Journal

Cell Reports

Abstract

TREX2, a 3'-5' exonuclease, is a part of the DNA damage tolerance (DDT) pathway that stabilizes replication forks (RFs) by ubiquitinating PCNA along with the ubiquitin E3 ligase RAD18 and other DDT factors. Mismatch repair (MMR) corrects DNA polymerase errors, including base mismatches and slippage. Here we demonstrate that TREX2 deletion reduces mutations in cells upon exposure to genotoxins, including those that cause base lesions and DNA polymerase slippage. Importantly, we show that TREX2 generates most of the spontaneous mutations in MMR-mutant cells derived from mice and people. TREX2-induced mutagenesis is dependent on the nuclease and DNA-binding attributes of TREX2. RAD18 deletion also reduces spontaneous mutations in MMR-mutant cells, albeit to a lesser degree. Inactivation of both MMR and TREX2 additively increases RF stalls, while it decreases DNA breaks, consistent with a synthetic phenotype.

Keywords

Humans, Mice, Animals, Mutagens, Mutagenesis, DNA-Directed DNA Polymerase, Mutation, Ubiquitin, DNA Replication, Exodeoxyribonucleases, Phosphoproteins, DNA-Binding Proteins, Ubiquitin-Protein Ligases

DOI

10.1016/j.celrep.2023.113637

PMID

38175749

PMCID

PMC10883656

PubMedCentral® Posted Date

2-22-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes