The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis
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The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis. / Burkovics, Peter; Dome, Lili; Juhasz, Szilvia; Altmannova, Veronika; Sebesta, Marek; Pacesa, Martin; Fugger, Kasper; Sorensen, Claus Storgaard; Lee, Marietta Y W T; Haracska, Lajos; Krejci, Lumir.
I: Nucleic Acids Research, Bind 44, Nr. 7, 20.04.2016, s. 3176-89.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
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
N1 - © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.
PY - 2016/4/20
Y1 - 2016/4/20
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
VL - 44
SP - 3176
EP - 3189
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 7
ER -
ID: 165717288