POLI

POLI encodes DNA polymerase iota, an error-prone translesion synthesis (TLS) polymerase that protects cells from genotoxic stress through both catalytic and protein-stabilizing functions (PMID:32635723, PMID:37558683). The recombinant enzyme carries both TLS polymerase and deoxyribose phosphate (dRP) lyase activities, but structure-function analysis of missense variants establishes that it is the TLS polymerase activity—not dRP lyase activity—that determines POLI's protective role against oxidative DNA damage: variants retaining polymerase activity rescue H2O2 sensitivity of POLI-knockout cells while catalytically dead variants do not (PMID:32635723). Beyond direct lesion bypass, POLI stabilizes the recombinase RAD51 by competitively binding RAD51 and blocking its interaction with the E3 ubiquitin ligase XIAP, thereby preventing RAD51 ubiquitination and degradation; through this mechanism POLI supports homologous recombination and confers radioresistance (PMID:37558683).

1. 2003 Medium

   Established that the Poli gene product is an error-prone polymerase whose misincorporation activity can be mutagenic in vivo, linking its biochemical infidelity to tumor initiation.

   Evidence In vitro polymerase activity characterization plus genetic correlation of Poli polymorphisms with Kras2 mutation frequency in chimeric mouse lung tumors

   PMID:12700672

   Open questions at the time

   • Correlation between polymorphisms and tumor frequency does not prove a direct causal mechanism
   • Mouse ortholog; human POLI not assayed here
   • No structural basis for the misincorporation preference
2. 2020 High

   Resolved which of POLI's two enzymatic activities underlies its protective function, showing the TLS polymerase activity—not dRP lyase activity—guards cells against oxidative damage.

   Evidence In vitro kinetic and dRP lyase assays on recombinant variants combined with CRISPR/Cas9 knockout and variant rescue of H2O2 sensitivity in HEK293 cells

   PMID:32635723

   Open questions at the time

   • Physiological lesions bypassed in vivo not fully cataloged beyond 8-oxoG
   • Role of dRP lyase activity, if any, remains undefined
   • Single cell line tested
3. 2023 Medium

   Revealed a non-catalytic role for POLI in homologous recombination by showing it stabilizes RAD51 through competitive blockade of XIAP-mediated ubiquitination, explaining POLI-dependent radioresistance.

   Evidence Reciprocal Co-IP/competitive binding, ubiquitination assays, HR/NHEJ reporters, and DNA damage foci/comet assays after irradiation in ESCC cells with knockdown

   PMID:37558683

   Open questions at the time

   • Whether RAD51 stabilization requires POLI catalytic activity is unresolved
   • Single cancer cell context (ESCC)
   • Direct competition with XIAP not confirmed structurally
4. 2025 Low

   Implicated POLI in repeat-tract repair, showing its interaction with DCLRE1A channels break repair toward inverted-repeat formation via template switching.

   Evidence CRISPRi screen, Co-IP, and sequencing of Cas12a-induced editing outcomes at CAG repeats (preprint)

   PMID:bio_10.1101_2025.11.18.689026

   Open questions at the time

   • Preprint, single lab, not peer reviewed
   • Interaction inferred from screen and co-IP without reciprocal/structural validation
   • Mechanism of template switching only partially defined

• How POLI's catalytic TLS function and its non-catalytic protein-stabilizing/scaffolding roles are coordinated within the same cell remains unknown.
• No structural model integrating polymerase, dRP lyase, RAD51-binding, and DCLRE1A-binding functions
• Regulation of POLI recruitment to different repair pathways undefined
• Physiological substrate spectrum incompletely mapped