TY - JOUR
T1 - Inhibition of homologous recombination by the PCNA-interacting protein PARI
AU - Moldovan, George Lucian
AU - Dejsuphong, Donniphat
AU - Petalcorin, Mark I.R.
AU - Hofmann, Kay
AU - Takeda, Shunichi
AU - Boulton, Simon J.
AU - D'Andrea, Alan D.
N1 - Funding Information:
We would like to thank Maria Jasin for the DR-GFP reporter, Lisa Moreau for chromosome aberration analyses, Kailin Yang for initial PARI cloning, and Dipanjan Chowdhury, Geoffrey Shapiro, Timur Yusufzai, Deepa Kushwaha, Stefan Muller, Kevin O'Connor, Younghoon Kee, Patrizia Vinciguerra, and Hyungjin Kim for materials and advice. G.L.M. is supported by postdoctoral fellowships from the International Human Frontiers Science Program and the Susan G. Komen Breast Cancer Foundation. This study was supported by National Institutes of Health grants R01DK43889, R01HL52725, P01HL048546, and P01CA092584 to A.D.D. and by Deutsche Forschungsgemeinschaft priority program SPP1365 to K.H.
PY - 2012/1/13
Y1 - 2012/1/13
N2 - Inappropriate homologous recombination (HR) causes genomic instability and cancer. In yeast, the UvrD family helicase Srs2 is recruited to sites of DNA replication by SUMO-modified PCNA, where it acts to restrict HR by disassembling toxic RAD51 nucleofilaments. How human cells control recombination at replication forks is unknown. Here, we report that the protein PARI, containing a UvrD-like helicase domain, is a PCNA-interacting partner required for preservation of genome stability in human and DT40 chicken cells. Using cell-based and biochemical assays, we show that PARI restricts unscheduled recombination by interfering with the formation of RAD51-DNA HR structures. Finally, we show that PARI knockdown suppresses the genomic instability of Fanconi Anemia/BRCA pathway-deficient cells. Thus, we propose that PARI is a long sought-after factor that suppresses inappropriate recombination events at mammalian replication forks.
AB - Inappropriate homologous recombination (HR) causes genomic instability and cancer. In yeast, the UvrD family helicase Srs2 is recruited to sites of DNA replication by SUMO-modified PCNA, where it acts to restrict HR by disassembling toxic RAD51 nucleofilaments. How human cells control recombination at replication forks is unknown. Here, we report that the protein PARI, containing a UvrD-like helicase domain, is a PCNA-interacting partner required for preservation of genome stability in human and DT40 chicken cells. Using cell-based and biochemical assays, we show that PARI restricts unscheduled recombination by interfering with the formation of RAD51-DNA HR structures. Finally, we show that PARI knockdown suppresses the genomic instability of Fanconi Anemia/BRCA pathway-deficient cells. Thus, we propose that PARI is a long sought-after factor that suppresses inappropriate recombination events at mammalian replication forks.
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U2 - 10.1016/j.molcel.2011.11.010
DO - 10.1016/j.molcel.2011.11.010
M3 - Article
C2 - 22153967
AN - SCOPUS:84855901029
VL - 45
SP - 75
EP - 86
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 1
ER -
