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TREX2 Exonuclease Causes Spontaneous Mutations and Stress-Induced Replication Fork Defects in Cells Expressing RAD51(K133A)

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KO Jun Ho SON Mi Young ZHOU Qing MOLNÁROVÁ Lucia SONG Lambert MLCOUSKOVA Jarmila JEKABSONS Atis MONTAGNA Cristina KREJČÍ Lumír HASTY Paul

Rok publikování 2020
Druh Článek v odborném periodiku
Časopis / Zdroj Cell Reports
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
www https://doi.org/10.1016/j.celrep.2020.108543
Doi http://dx.doi.org/10.1016/j.celrep.2020.108543
Klíčová slova DNA damage tolerance; homologous recombination; double-strand break repair; replication fork maintenance; genomic instability
Popis 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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