title: Roles for APRIN (PDS5B) in homologous recombination and in ovarian cancer prediction.
abstract: APRIN (PDS5 cohesin associated factor B) interacts with both the cohesin complex and the BRCA2 tumor suppressor. How APRIN influences cohesion and DNA repair processes is not well understood. Here, we show that APRIN is recruited to DNA damage sites. We find that APRIN interacts directly with RAD51, PALB2 and BRCA2. APRIN stimulates RAD51-mediated DNA strand invasion. APRIN also binds DNA with an affinity for D-loop structures and single-strand (ss) DNA. APRIN is a new homologous recombination (HR) mediator as it counteracts the RPA inhibitory effect on RAD51 loading to ssDNA. We show that APRIN strongly improves the annealing of complementary-strand DNA and that it can stimulate this process in synergy with BRCA2. Unlike cohesin constituents, its depletion has no impact on class switch recombination, supporting a specific role for this protein in HR. Furthermore, we show that low APRIN expression levels correlate with a better survival in ovarian cancer patients and that APRIN depletion sensitizes cells to the PARP inhibitor Olaparib in xenografted zebrafish. Our findings establish APRIN as an important and specific actor of HR, with cohesin-independent functions.
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Couturier
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada; Institut du cancer de Montréal, Montréal, QC H2X 0A9, Canada.|Department of Medicine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
authors.forename: Hubert
authors.initials: H
authors.lastname: Fleury
authors.affiliation: Institut de Recherches Cliniques de Montréal and Department of Medicine, Université de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Patenaude
authors.affiliation: Dalhousie University, Faculty of Medicine, Department of Pathology, Halifax, NS B3H 4R2, Canada.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bentley
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Amélie
authors.initials: A
authors.lastname: Rodrigue
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Coulombe
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Joshi
authors.initials: J
authors.lastname: Niraj
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Joris
authors.initials: J
authors.lastname: Pauty
authors.affiliation: Dalhousie University, Faculty of Medicine, Departments of Microbiology and Immunology, Pediatrics and Pathology, Halifax, NS B3H 4R2, Canada.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Berman
authors.affiliation: Dalhousie University, Faculty of Medicine, Department of Pathology, Halifax, NS B3H 4R2, Canada.
authors.forename: Graham
authors.initials: G
authors.lastname: Dellaire
authors.affiliation: Institut de Recherches Cliniques de Montréal and Department of Medicine, Université de Montréal, Montréal, Québec H2W 1R7, Canada.
authors.forename: Javier M
authors.initials: JM
authors.lastname: Di Noia
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada; Institut du cancer de Montréal, Montréal, QC H2X 0A9, Canada.|Department of Medicine, Université de Montréal, Montréal, QC H2X 0A9, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.affiliation: Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada Jean-Yves.Masson@fmed.ulaval.ca.|Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Québec City, QC G1V 0A6, Canada.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Masson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D024682:BRCA2 Protein / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D021381:Protein Transport; D012372:ROC Curve; D051135:Rad51 Recombinase / Q000378:metabolism; D059767:Recombinational DNA Repair; D065310:Squamous Intraepithelial Lesions of the Cervix / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; C118660:PDS5B protein, human; D010793:Phthalazines; D010879:Piperazines; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C521013:veliparib; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C531550:olaparib