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J Biol Chem. 2014 Aug 29;289(35):24617-29. doi: 10.1074/jbc.M114.566141. Epub 2014 Jul 11.

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

Author information

1
From the Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, the Departments of Radiation Oncology.
2
the Developmental Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065.
3
the Department of Molecular Biology and Biochemistry, School of Arts and Sciences, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854.
4
the Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and.
5
Pediatrics, and.
6
the Department of Molecular and Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, Ohio 43210.
7
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.
8
From the Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, Pediatrics, and.
9
From the Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, the Departments of Radiation Oncology, xiabi@cinj.rutgers.edu.

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.

KEYWORDS:

BRCA1; BRCA2; DNA Damage Response; FANCN; Fanconi Anemia; Homologous Recombination; Male Infertility; Meiosis; PALB2; Spermatogenesis

PMID:
25016020
PMCID:
PMC4148885
DOI:
10.1074/jbc.M114.566141
[Indexed for MEDLINE]
Free PMC Article
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