TREX2 deficiency suppresses spontaneous and genotoxin-associated mutagenesis
Year: 2024
Type: article
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.
Source: Cell Reports
Authors: Teresa Marple, Mi Young Son, Xiaodong Cheng, Jun Ho Ko, Patrick Sung, Paul Hasty
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: Welch Foundation, Cancer Prevention and Research Institute of Texas, Edward P. Evans Foundation, Gray Foundation, National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of Environmental Health Sciences, Institute for Integration of Medicine and Science
Awards: G1351874825, Study DNA repair in preventing MDS and AML after radiation and benzene exposure, G2247619688, TREX2 Inhibitors to Treat BCR-ABL-Cancers, G4356167108, G4752449799, UTHSCSA Cancer Research Training Program, DNA Repair, Mutations and Cellular Aging, How does TREX2 maintain and alter chromosomes?, Mechanisms of DNA Homology-directed Genome Repair and Tumor Suppression
OpenAlex ID: W4390546679