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.

Základní údaje

Originální název

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

Autoři

BURKOVICS, Peter (348 Maďarsko, domácí), Lili DOME (348 Maďarsko), Szilvia JUHASZ (348 Maďarsko), Veronika ALTMANNOVÁ (203 Česká republika, domácí), Marek ŠEBESTA (703 Slovensko, domácí), Martin PAČESA (703 Slovensko, domácí), Kasper FUGGER (208 Dánsko), Claus Storgaard SORENSEN (208 Dánsko), Marietta Y.W.T. LEE (840 Spojené státy), Lajos HARACSKA (348 Maďarsko) a Lumír KREJČÍ (203 Česká republika, garant, domácí)

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

Genetika a molekulární biologie

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 10.162

Kód RIV

RIV/00216224:14110/16:00088204

Organizační jednotka

Lékařská fakulta

DOI

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

UT WoS

000375800200027

Klíčová slova anglicky

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

Štítky

EL OK, podil

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 28. 11. 2016 16:02, Ing. Mgr. Věra Pospíšilíková

Anotace

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.

Návaznosti

GAP207/12/2323, projekt VaV

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

Investor: Grantová agentura ČR, Endonuleázová a translokázová aktivita v restrikčních-modifikačních komplexech typu I

GA13-26629S, projekt VaV

Název: SUMO a stability genomu

Investor: Grantová agentura ČR, SUMO a stability genomu

MUNI/M/1894/2014, interní kód MU

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

Investor: Masarykova univerzita, Development of new MUS81 nuclease inhibitors as chemical biology probe with clinical progression, INTERDISCIPLINARY - Mezioborové výzkumné projekty

ROZV/20/LF/2015, interní kód MU

Název: LF - Příspěvek IP 2015

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, LF - Příspěvek IP 2015

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 a 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, roč. 44, č. 7, s. 3176-3189. ISSN 0305-1048. Dostupné z: 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 a 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, roč.~44, č.~7, s.~3176-3189. ISSN~0305-1048. Dostupné z: https://dx.doi.org/10.1093/nar/gkw024.

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