TREX2 (three prime repair exonuclease 2) is a 3'-5' DNA exonuclease that plays critical roles in DNA repair, genomic stability, and cellular proliferation. The enzyme preferentially processes double-stranded DNA with mismatched 3' termini and functions as part of the DNA damage tolerance pathway by stabilizing replication forks through PCNA ubiquitination alongside RAD18 1. TREX2 prevents cytosolic DNA accumulation, thereby suppressing cGAS/STING pathway activation, which is crucial for immune surveillance 2. The protein's expression is epigenetically regulated through DNA methylation at an intragenic enhancer region, with methylation loss correlating with increased TREX2 expression and improved survival in laryngeal cancer patients 3. Paradoxically, TREX2 contributes significantly to spontaneous mutagenesis, particularly in mismatch repair-deficient cells, where its deletion substantially reduces mutation rates 1. TREX2 deficiency causes genomic instability including Robertsonian translocations and reduced cellular proliferation 4. Clinically, cisplatin chemotherapy depletes TREX2 levels, contributing to its cytotoxic effects beyond DNA cross-link formation 4. The enzyme can be co-expressed with other exonucleases to mitigate mitochondrial DNA transfer to nuclear genomes during genome editing procedures 5.