title: APRIN is a cell cycle specific BRCA2-interacting protein required for genome integrity and a predictor of outcome after chemotherapy in breast cancer.
abstract: Mutations in BRCA2 confer an increased risk of cancer development, at least in part because the BRCA2 protein is required for the maintenance of genomic integrity. Here, we use proteomic profiling to identify APRIN (PDS5B), a cohesion-associated protein, as a BRCA2-associated protein. After exposure of cells to hydroxyurea or aphidicolin, APRIN and other cohesin components associate with BRCA2 in early S-phase. We demonstrate that APRIN expression is required for the normal response to DNA-damaging agents, the nuclear localisation of RAD51 and BRCA2 and efficient homologous recombination. The clinical significance of these findings is indicated by the observation that the BRCA2/APRIN interaction is compromised by BRCA2 missense variants of previously unknown significance and that APRIN expression levels are associated with histological grade in breast cancer and the outcome of breast cancer patients treated with DNA-damaging chemotherapy.
authors.affiliation: Cancer Research UK Gene Function and Regulation Group, London, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brough
authors.forename: Ilirjana
authors.initials: I
authors.lastname: Bajrami
authors.forename: Radost
authors.initials: R
authors.lastname: Vatcheva
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D024682:BRCA2 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004358:Drug Therapy / Q000379:methods*; D006801:Humans; D011379:Prognosis; D025941:Protein Interaction Mapping; D020543:Proteome / Q000032:analysis; D051135:Rad51 Recombinase / Q000378:metabolism; D011995:Recombination, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004268:DNA-Binding Proteins; C118660:PDS5B protein, human; D020543:Proteome; D014157:Transcription Factors; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D045643:DNA Repair Enzymes