TREX2 deficiency suppresses spontaneous and genotoxin-associated mutagenesis
Teresa Marple,
Mi Young Son,
Xiaodong Cheng,
Jun Ho Ko,
Patrick Sung,
Paul Hasty
Affiliations
Teresa Marple
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Mi Young Son
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Xiaodong Cheng
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Jun Ho Ko
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Patrick Sung
Department of Biochemistry and Structural Biology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; The Mays Cancer Center, University of Texas Health San Antonio MD Anderson Cancer Center, San Antonio, TX 78229, USA; Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Paul Hasty
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health San Antonio, San Antonio, TX 78229, USA; The Mays Cancer Center, University of Texas Health San Antonio MD Anderson Cancer Center, San Antonio, TX 78229, USA; Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Corresponding author
Summary: 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.
