TREX2 deficiency suppresses spontaneous and genotoxin-associated mutagenesis

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number113637
JournalCell Reports
Issue number1
StatePublished - Jan 23 2024


  • CP: Molecular biology
  • DNA damage tolerance
  • TREX2
  • mismatch repair
  • replication fork maintenance

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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