
Faculty, Staff and Student Publications
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
Graphical Abstract
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons