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

Peter Burkovics; Lili Dome; Szilvia Juhasz; Veronika Altmannova; Marek Sebesta; Martin Pacesa; Kasper Fugger; Claus Storgaard Sorensen; Marietta Y W T Lee; Lajos Haracska; Lumir Krejci

doi:10.1093/nar/gkw024

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

Peter Burkovics, Lili Dome, Szilvia Juhasz, Veronika Altmannova, Marek Sebesta, Martin Pacesa, Kasper Fugger, Claus Storgaard Sorensen, Marietta Y W T Lee, Lajos Haracska, Lumir Krejci

23 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Nucleic Acids Research
Vol/bind	44
Udgave nummer	7
Sider (fra-til)	3176-89
Antal sider	14
ISSN	0305-1048
DOI	https://doi.org/10.1093/nar/gkw024
Status	Udgivet - 20 jan. 2016

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10.1093/nar/gkw024Licens: CC BY-NC

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

abstract = "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.",

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T1 - The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis

AU - Burkovics, Peter

AU - Dome, Lili

AU - Juhasz, Szilvia

AU - Altmannova, Veronika

AU - Sebesta, Marek

AU - Pacesa, Martin

AU - Fugger, Kasper

AU - Sorensen, Claus Storgaard

AU - Lee, Marietta Y W T

AU - Haracska, Lajos

AU - Krejci, Lumir

PY - 2016/1/20

Y1 - 2016/1/20

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.

AB - 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.

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/nar/gkw024

DO - 10.1093/nar/gkw024

M3 - Journal article

C2 - 26792895

SN - 0305-1048

VL - 44

SP - 3176

EP - 3189

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 7

ER -

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

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