Publication details

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

Authors

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

Year of publication 2020
Type Article in Periodical
Magazine / Source Cell Reports
MU Faculty or unit

Faculty of Science

Citation
Web https://doi.org/10.1016/j.celrep.2020.108543
Doi http://dx.doi.org/10.1016/j.celrep.2020.108543
Keywords DNA damage tolerance; homologous recombination; double-strand break repair; replication fork maintenance; genomic instability
Description 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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