The PCNA-associated protein PARI negatively regulates
homologous recombination via the inhibition of DNA repair
synthesis

J 2016

The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis

BURKOVICS, Peter, Lili DOME, Szilvia JUHASZ, Veronika ALTMANNOVÁ, Marek ŠEBESTA et. al.

Basic information

Original name

The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis

Authors

BURKOVICS, Peter (348 Hungary, belonging to the institution), Lili DOME (348 Hungary), Szilvia JUHASZ (348 Hungary), Veronika ALTMANNOVÁ (203 Czech Republic, belonging to the institution), Marek ŠEBESTA (703 Slovakia, belonging to the institution), Martin PAČESA (703 Slovakia, belonging to the institution), Kasper FUGGER (208 Denmark), Claus Storgaard SORENSEN (208 Denmark), Marietta Y.W.T. LEE (840 United States of America), Lajos HARACSKA (348 Hungary) and Lumír KREJČÍ (203 Czech Republic, guarantor, belonging to the institution)

Edition

Nucleic Acids Research, Oxford, Oxford University Press, 2016, 0305-1048

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

Genetics and molecular biology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 10.162

RIV identification code

RIV/00216224:14110/16:00088204

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1093/nar/gkw024

UT WoS

000375800200027

Keywords in English

CELL NUCLEAR ANTIGEN; UBIQUITIN-BINDING DOMAINS; DAMAGE TOLERANCE PATHWAY; BLOOMS-SYNDROME HELICASE; SACCHAROMYCES-CEREVISIAE; REPLICATION FORK; POSTREPLICATION REPAIR; TRANSLESION SYNTHESIS; GENOMIC STABILITY; SUMO MODIFICATION

Abstract

V originále

Successful and accurate completion of the replication of damage-containing DNA requires mainly recombination and RAD18-dependent DNA damage tolerance pathways. RAD18 governs at least two distinct mechanisms: translesion synthesis (TLS) and template switching (TS)-dependent pathways. Whereas TS is mainly error-free, TLS can work in an error-prone manner and, as such, the regulation of these pathways requires tight control to prevent DNA errors and potentially oncogenic transformation and tumorigenesis. In humans, the PCNA-associated recombination inhibitor (PARI) protein has recently been shown to inhibit homologous recombination (HR) events. Here, we describe a biochemical mechanism in which PARI functions as an HR regulator after replication fork stalling and during double-strand break repair. In our reconstituted biochemical system, we show that PARI inhibits DNA repair synthesis during recombination events in a PCNA interaction-dependent way but independently of its UvrD-like helicase domain. In accordance, we demonstrate that PARI inhibits HR in vivo, and its knockdown suppresses the UV sensitivity of RAD18-depleted cells. Our data reveal a novel human regulatory mechanism that limits the extent of HR and represents a new potential target for anticancer therapy.

Links

GAP207/12/2323, research and development project

Name: Endonuleazová a translokázová aktivita v restričních-modifikáčních komplexéch typu I

Investor: Czech Science Foundation

GA13-26629S, research and development project

Name: SUMO a stability genomu

Investor: Czech Science Foundation

MUNI/M/1894/2014, interní kód MU

Name: Development of new MUS81 nuclease inhibitors as chemical biology probe with clinical progression

Investor: Masaryk University, INTERDISCIPLINARY - Interdisciplinary research projects

ROZV/20/LF/2015, interní kód MU

Name: LF - Příspěvek IP 2015

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

BURKOVICS, Peter, Lili DOME, Szilvia JUHASZ, Veronika ALTMANNOVÁ, Marek ŠEBESTA, Martin PAČESA, Kasper FUGGER, Claus Storgaard SORENSEN, Marietta Y.W.T. LEE, Lajos HARACSKA and Lumír KREJČÍ. The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis. Nucleic Acids Research. Oxford: Oxford University Press, 2016, vol. 44, No 7, p. 3176-3189. ISSN 0305-1048. Available from: https://dx.doi.org/10.1093/nar/gkw024.

@article{1355901,
   author = {Burkovics, Peter and Dome, Lili and Juhasz, Szilvia and Altmannová, Veronika and Šebesta, Marek and Pačesa, Martin and Fugger, Kasper and Sorensen, Claus Storgaard and Lee, Marietta Y.W.T. and Haracska, Lajos and Krejčí, Lumír},
   article_location = {Oxford},
   article_number = {7},
   doi = {http://dx.doi.org/10.1093/nar/gkw024},
   keywords = {CELL NUCLEAR ANTIGEN; UBIQUITIN-BINDING DOMAINS; DAMAGE TOLERANCE PATHWAY; BLOOMS-SYNDROME HELICASE; SACCHAROMYCES-CEREVISIAE; REPLICATION FORK; POSTREPLICATION REPAIR; TRANSLESION SYNTHESIS; GENOMIC STABILITY; SUMO MODIFICATION},
   language = {eng},
   issn = {0305-1048},
   journal = {Nucleic Acids Research},
   title = {The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis},
   volume = {44},
   year = {2016}
}

TY  - JOUR
ID  - 1355901
AU  - Burkovics, Peter - Dome, Lili - Juhasz, Szilvia - Altmannová, Veronika - Šebesta, Marek - Pačesa, Martin - Fugger, Kasper - Sorensen, Claus Storgaard - Lee, Marietta Y.W.T. - Haracska, Lajos - Krejčí, Lumír
PY  - 2016
TI  - The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis
JF  - Nucleic Acids Research
VL  - 44
IS  - 7
SP  - 3176-3189
EP  - 3176-3189
PB  - Oxford University Press
SN  - 03051048
KW  - CELL NUCLEAR ANTIGEN
KW  - UBIQUITIN-BINDING DOMAINS
KW  - DAMAGE TOLERANCE PATHWAY
KW  - BLOOMS-SYNDROME HELICASE
KW  - SACCHAROMYCES-CEREVISIAE
KW  - REPLICATION FORK
KW  - POSTREPLICATION REPAIR
KW  - TRANSLESION SYNTHESIS
KW  - GENOMIC STABILITY
KW  - SUMO MODIFICATION
N2  - Successful and accurate completion of the replication of damage-containing DNA requires mainly recombination and RAD18-dependent DNA damage tolerance pathways. RAD18 governs at least two distinct mechanisms: translesion synthesis (TLS) and template switching (TS)-dependent pathways. Whereas TS is mainly error-free, TLS can work in an error-prone manner and, as such, the regulation of these pathways requires tight control to prevent DNA errors and potentially oncogenic transformation and tumorigenesis. In humans, the PCNA-associated recombination inhibitor (PARI) protein has recently been shown to inhibit homologous recombination (HR) events. Here, we describe a biochemical mechanism in which PARI functions as an HR regulator after replication fork stalling and during double-strand break repair. In our reconstituted biochemical system, we show that PARI inhibits DNA repair synthesis during recombination events in a PCNA interaction-dependent way but independently of its UvrD-like helicase domain. In accordance, we demonstrate that PARI inhibits HR in vivo, and its knockdown suppresses the UV sensitivity of RAD18-depleted cells. Our data reveal a novel human regulatory mechanism that limits the extent of HR and represents a new potential target for anticancer therapy.
ER  -

BURKOVICS, Peter, Lili DOME, Szilvia JUHASZ, Veronika ALTMANNOVÁ, Marek ŠEBESTA, Martin PAČESA, Kasper FUGGER, Claus Storgaard SORENSEN, Marietta Y.W.T. LEE, Lajos HARACSKA and Lumír KREJČÍ. The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis. \textit{Nucleic Acids Research}. Oxford: Oxford University Press, 2016, vol.~44, No~7, p.~3176-3189. ISSN~0305-1048. Available from: https://dx.doi.org/10.1093/nar/gkw024.

Detailed Information on Publication Record