Male fertility defect associated with disrupted BRCA1-PALB2 interaction in mice Journal Article


Authors: Simhadri, S.; Peterson, S.; Patel, D. S.; Huo, Y.; Cai, H.; Bowman-Colin, C.; Miller, S.; Ludwig, T.; Ganesan, S.; Bhaumik, M.; Bunting, S. F.; Jasin, M.; Xia, B.
Article 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. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Keywords: cell death; mammals; crosslinker; chromosomes; embryonic lethality; repair; male fertility; defects; dna double strand breaks; sex chromosomes; biallelic mutations; complex formations; fanconi anemias
Journal Title: Journal of Biological Chemistry
Volume: 289
Issue: 35
ISSN: 0021-9258
Publisher: American Society for Biochemistry and Molecular Biology  
Date Published: 2014-08-29
Start Page: 24617
End Page: 24629
Language: English
DOI: 10.1074/jbc.M114.566141
PROVIDER: scopus
PMCID: PMC4148885
PUBMED: 25016020
DOI/URL:
Notes: Export Date: 1 October 2014 -- Source: Scopus
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MSK Authors
  1. Maria Jasin
    230 Jasin