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Updated: Jul 6, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
TREX2 deficiency suppresses spontaneous and genotoxin-associated mutagenesis
Teresa Marple1, Mi Young Son2, Xiaodong Cheng3
1Department 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.
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.
Insights
The DNA repair enzyme TREX2 significantly contributes to spontaneous mutations in cells lacking mismatch repair (MMR). Deleting TREX2 reduces mutations caused by DNA damage, highlighting its role in genome stability.
Area of Science:
- Molecular Biology
- Genetics
- DNA Repair
Background:
- The DNA damage tolerance (DDT) pathway stabilizes replication forks (RFs) via factors like TREX2, RAD18, and PCNA ubiquitination.
- Mismatch repair (MMR) corrects DNA polymerase errors, including base mismatches and slippage.
Purpose of the Study:
- To investigate the role of TREX2 in mutagenesis, particularly in the context of MMR deficiency.
- To determine if TREX2 contributes to spontaneous mutations and genotoxin-induced mutations.
Main Methods:
- Utilizing cell models with and without TREX2 and MMR.
- Assessing mutation rates after exposure to genotoxins.
- Evaluating replication fork stability and DNA breaks.
Main Results:
- TREX2 deletion reduced mutations from genotoxins causing base lesions and polymerase slippage.
- TREX2 was identified as the primary source of spontaneous mutations in MMR-deficient cells.
- TREX2's nuclease and DNA-binding activities are crucial for its mutagenic effect.
- RAD18 deletion also decreased spontaneous mutations in MMR-mutant cells.
- Simultaneous inactivation of MMR and TREX2 led to increased RF stalls and decreased DNA breaks.
Conclusions:
- TREX2 plays a significant role in generating spontaneous mutations in MMR-deficient cells.
- TREX2 contributes to genome instability by promoting mutations, especially under DNA-damaging conditions.
- Targeting TREX2 could be a strategy to reduce mutagenesis in certain cellular contexts.
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