title: Inhibition of homologous recombination by the PCNA-interacting protein PARI.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: George-Lucian
authors.initials: GL
authors.lastname: Moldovan
authors.forename: Donniphat
authors.initials: D
authors.lastname: Dejsuphong
authors.forename: Mark I R
authors.initials: MI
authors.lastname: Petalcorin
authors.forename: Kay
authors.initials: K
authors.lastname: Hofmann
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takeda
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Boulton
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002645:Chickens / Q000235:genetics; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D042822:Genomic Instability; D057809:HEK293 Cells; D006367:HeLa Cells; D059765:Homologous Recombination / Q000502:physiology*; D006801:Humans; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C556015:PARPBP protein, human; D018809:Proliferating Cell Nuclear Antigen; C495153:RAD51 protein, human; D051135:Rad51 Recombinase