title: Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2.
abstract: BRCA2 mutations predispose carriers to breast and ovarian cancer and can also cause other cancers and Fanconi anemia. BRCA2 acts as a "caretaker" of genome integrity by enabling homologous recombination (HR)-based, error-free DNA double-strand break repair (DSBR) and intra-S phase DNA damage checkpoint control. Described here is the identification of PALB2, a BRCA2 binding protein. PALB2 colocalizes with BRCA2 in nuclear foci, promotes its localization and stability in key nuclear structures (e.g., chromatin and nuclear matrix), and enables its recombinational repair and checkpoint functions. In addition, multiple, germline BRCA2 missense mutations identified in breast cancer patients but of heretofore unknown biological/clinical consequence appear to disrupt PALB2 binding and disable BRCA2 HR/DSBR function. Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and ensures its tumor suppression function.
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115.
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115.
authors.forename: Qing
authors.initials: Q
authors.lastname: Sheng
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakanishi
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, Minnesota 55905.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ohashi
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, Minnesota 55905.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021.
authors.forename: Nicole
authors.initials: N
authors.lastname: Christ
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115.
authors.forename: Xinggang
authors.initials: X
authors.lastname: Liu
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021.
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, Minnesota 55905.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
authors.affiliation: Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115. Electronic address: david_livingston@dfci.harvard.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Livingston
mesh_terms: D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D015530:Nuclear Matrix / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011995:Recombination, Genetic / Q000235:genetics; D016196:S Phase / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; D002843:Chromatin; D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins