Journal
CELL REPORTS
Volume 33, Issue 12, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108543
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Funding
- National Institutes of Health (USA) [1 R01 ES022054-04, 1 R01 CA188032-01, 1 P01AG017242-17A1]
- Evans Foundation (USA)
- IIMS pilot (USA)
- CPRIT research training award (USA) [RP170345]
- Albert Einstein Cancer Center Support Grant of the National Institutes of Health [P30CA013330]
- Wellcome Trust (United Kingdom) [206292/E/17/Z]
- Czech Science Foundation (Czechia) [GACR 17-17720S, 21-22593X]
- National Program of Sustainability II (MEYS CR) [LQ1605]
- Masaryk University [MUNI/G/1594/2019]
- Operational Programme Research, Development and Education-Project Postdoc@MUNI [CZ.02.2.69/0.0/0.0/16_027/0008360]
- Wellcome Trust [206292/E/17/Z] Funding Source: Wellcome Trust
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DNA damage tolerance (DDT) and homologous recombination (HR) stabilize replication forks (RFs). RAD18/UBC13/three prime repair exonuclease 2 (TREX2)-mediated proliferating cell nuclear antigen (PCNA) ubiqui-tination is central to DDT, an error-prone lesion bypass pathway. RAD51 is the recombinase for HR. The RAD51(K133A) mutation increased spontaneous mutations and stress-induced RF stalls and nascent strand degradation. Here, we report in RAD51(K133A) cells that this phenotype is reduced by expressing a TREX2 H188A mutation that deletes its exonuclease activity. In RAD51(K133A) cells, knocking out RAD18 or overexpressing PCNA reduces spontaneous mutations, while expressing ubiquitination-incompetent PCNA(K164R )increases mutations, indicating DDT as causal. Deleting TREX2 in cells deficient for the RF maintenance proteins poly(ADP-ribose) polymerase 1 (PARP1) or FANCB increased nascent strand degradation that was rescued by TREX2(H188A), implying that TREX2 prohibits degradation independent of catalytic activity. A possible explanation for this occurrence is that TREX2(H188A) associates with UBC13 and ubiquitinates PCNA, suggesting a dual role for TREX2 in RF maintenance.
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