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

J 2020

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

KO, Jun Ho, Mi Young SON, Qing ZHOU, Lucia MOLNÁROVÁ, Lambert SONG et. al.

Basic information

Original name

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

Authors

KO, Jun Ho, Mi Young SON, Qing ZHOU, Lucia MOLNÁROVÁ (703 Slovakia, belonging to the institution), Lambert SONG, Jarmila MLCOUSKOVA, Atis JEKABSONS (428 Latvia, belonging to the institution), Cristina MONTAGNA, Lumír KREJČÍ (203 Czech Republic, belonging to the institution) and Paul HASTY

Edition

Cell Reports, Cambridge, Cell Press, 2020, 2211-1247

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10603 Genetics and heredity

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 9.423

RIV identification code

RIV/00216224:14310/20:00114676

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1016/j.celrep.2020.108543

UT WoS

000601399100020

Keywords in English

DNA damage tolerance; homologous recombination; double-strand break repair; replication fork maintenance; genomic instability

Abstract

V originále

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.

Links

EF16_027/0008360, research and development project

Name: Postdoc@MUNI

GA17-17720S, research and development project

Name: Vnitřní vlastnosti RAD51 vlákna a jeho biologické regulace

Investor: Czech Science Foundation

MUNI/G/1594/2019, interní kód MU

Name: RecQ4 – a protein hub required for proper replication and recombination and its implications in Rothmund-Thomson Syndrome

Investor: Masaryk University, INTERDISCIPLINARY - Interdisciplinary research projects

21-22593X, interní kód MU

Name: Identification and characterization of proteins involved in metabolism of G-quadruplexes and R-loops and molecular mechanisms of their relationship with replication

Investor: Czech Science Foundation

Citovat

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). 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.

@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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