REV3L encodes the catalytic subunit of DNA polymerase zeta (Pol ζ), an error-prone polymerase essential for translesion DNA synthesis (TLS) that allows cells to replicate damaged DNA templates 1. The protein lacks 3'-5' exonuclease proofreading activity and works sequentially with other DNA polymerases to bypass various DNA lesions, including those caused by UV radiation and cisplatin 21. REV3L undergoes sophisticated regulation through multiple mechanisms: it is normally kept inactive by autoinhibition, but ATR-mediated phosphorylation activates it during replication stress while simultaneously triggering its degradation 3. Additionally, site-specific cleavage by Taspase1 prevents ubiquitination and proteasome-mediated degradation, controlling protein stability 1. REV3L cooperates with MAD2L2/REV7 and REV1 to protect stalled replication forks from nucleolytic processing 4 and fills single-stranded DNA gaps through RAD18-dependent pathways 5. Disease relevance includes de novo mutations causing Möbius syndrome, a neurological disorder characterized by facial nerve paralysis 6, though recent systematic studies question the strength of this association 7. The tight regulation of REV3L activity is crucial for balancing its essential DNA repair function against its mutagenic potential.