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

Burkovics, Péter and Döme, Lili and Juhász, Szilvia and Altmannova, V. and Sebesta, M. and Haracska, Lajos (2016) The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis. NUCLEIC ACIDS RESEARCH, 44 (7). pp. 3176-3189. ISSN 0305-1048

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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.

Item Type: Article
Additional Information: Funding Details: GACR, Czech Science Foundation Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Szeged, 6726, Hungary Department of Biology, Masaryk University, Brno, 62500, Czech Republic National Centre for Biomolecular Research, Masaryk University, Brno, 62500, Czech Republic International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St Anne's University, Brno, 65691, Czech Republic Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, 2200, Denmark Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, United States Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX13RE, United Kingdom Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland Francis Crick Institute, Clare Hall Laboratory, South Mimms, EN63LD, United Kingdom Cited By :23 Export Date: 11 May 2021 CODEN: NARHA Correspondence Address: Burkovics, P.; Institute of Genetics, Hungary; email: burkovics.peter@brc.mta.hu
Subjects: Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 20 Sep 2021 14:30
Last Modified: 20 Sep 2021 14:30
URI: http://real.mtak.hu/id/eprint/129872

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