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@article{1728144,
author = {Ko, Jun Ho and Son, Mi Young and Zhou, Qing and Molnárová, Lucia and Song, Lambert and Mlcouskova, Jarmila and Jekabsons, Atis and Montagna, Cristina and Krejčí, Lumír and Hasty, Paul},
article_location = {Cambridge},
article_number = {12},
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},
language = {eng},
issn = {2211-1247},
journal = {Cell Reports},
title = {TREX2 Exonuclease Causes Spontaneous Mutations and Stress-Induced Replication Fork Defects in Cells Expressing RAD51(K133A)},
url = {https://doi.org/10.1016/j.celrep.2020.108543},
volume = {33},
year = {2020}
}
TY - JOUR
ID - 1728144
AU - Ko, Jun Ho - Son, Mi Young - Zhou, Qing - Molnárová, Lucia - Song, Lambert - Mlcouskova, Jarmila - Jekabsons, Atis - Montagna, Cristina - Krejčí, Lumír - Hasty, Paul
PY - 2020
TI - TREX2 Exonuclease Causes Spontaneous Mutations and Stress-Induced Replication Fork Defects in Cells Expressing RAD51(K133A)
JF - Cell Reports
VL - 33
IS - 12
SP - 1-18
EP - 1-18
PB - Cell Press
SN - 22111247
KW - DNA damage tolerance
KW - homologous recombination
KW - double-strand break repair
KW - replication fork maintenance
KW - genomic instability
UR - https://doi.org/10.1016/j.celrep.2020.108543
L2 - https://doi.org/10.1016/j.celrep.2020.108543
N2 - 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.
ER -
KO, Jun Ho, Mi Young SON, Qing ZHOU, Lucia MOLNÁROVÁ, Lambert SONG, Jarmila MLCOUSKOVA, Atis JEKABSONS, Cristina MONTAGNA, Lumír KREJČÍ and Paul HASTY. TREX2 Exonuclease Causes Spontaneous Mutations and Stress-Induced Replication Fork Defects in Cells Expressing RAD51(K133A). \textit{Cell Reports}. Cambridge: Cell Press, 2020, vol.~33, No~12, p.~1-18. ISSN~2211-1247. Available from: https://dx.doi.org/10.1016/j.celrep.2020.108543.
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