title: Male fertility defect associated with disrupted BRCA1-PALB2 interaction in mice.
abstract: PALB2 links BRCA1 and BRCA2 in homologous recombinational repair of DNA double strand breaks (DSBs). Mono-allelic mutations in PALB2 increase the risk of breast, pancreatic, and other cancers, and biallelic mutations cause Fanconi anemia (FA). Like Brca1 and Brca2, systemic knock-out of Palb2 in mice results in embryonic lethality. In this study, we generated a hypomorphic Palb2 allele expressing a mutant PALB2 protein unable to bind BRCA1. Consistent with an FA-like phenotype, cells from the mutant mice showed hypersensitivity and chromosomal breakage when treated with mitomycin C, a DNA interstrand crosslinker. Moreover, mutant males showed reduced fertility due to impaired meiosis and increased apoptosis in germ cells. Interestingly, mutant meiocytes showed a significant defect in sex chromosome synapsis, which likely contributed to the germ cell loss and fertility defect. Our results underscore the in vivo importance of the PALB2-BRCA1 complex formation in DSB repair and male meiosis.
authors.affiliation: From the Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, the Departments of Radiation Oncology.
authors.forename: Srilatha
authors.initials: S
authors.lastname: Simhadri
authors.affiliation: the Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065.
authors.forename: Shaun
authors.initials: S
authors.lastname: Peterson
authors.affiliation: the Department of Molecular Biology and Biochemistry, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Dharm S
authors.initials: DS
authors.lastname: Patel
authors.affiliation: From the Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, the Departments of Radiation Oncology.
authors.forename: Yanying
authors.initials: Y
authors.lastname: Huo
authors.affiliation: From the Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, the Departments of Radiation Oncology.
authors.forename: Hong
authors.initials: H
authors.lastname: Cai
authors.affiliation: the Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and.
authors.forename: Christian
authors.initials: C
authors.lastname: Bowman-Colin
authors.affiliation: Pediatrics, and.
authors.forename: Shoreh
authors.initials: S
authors.lastname: Miller
authors.affiliation: the Department of Molecular and Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.affiliation: From the Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901.
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: From the Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, Pediatrics, and.
authors.forename: Mantu
authors.initials: M
authors.lastname: Bhaumik
authors.affiliation: the Department of Molecular Biology and Biochemistry, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Bunting
authors.affiliation: the Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065.
authors.forename: Maria
authors.initials: M
authors.lastname: Jasin
authors.affiliation: From the Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, the Departments of Radiation Oncology, xiabi@cinj.rutgers.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D000076164:Fanconi Anemia Complementation Group N Protein; D059765:Homologous Recombination; D006801:Humans; D020287:In Situ Nick-End Labeling; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; D000076164:Fanconi Anemia Complementation Group N Protein; C552932:Palb2 protein, mouse; D025521:Tumor Suppressor Proteins
keywords: BRCA1; BRCA2; DNA Damage Response; FANCN; Fanconi Anemia; Homologous Recombination; Male Infertility; Meiosis; PALB2; Spermatogenesis