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

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.

Citation

Srilatha Simhadri, Shaun Peterson, Dharm S Patel, Yanying Huo, Hong Cai, Christian Bowman-Colin, Shoreh Miller, Thomas Ludwig, Shridar Ganesan, Mantu Bhaumik, Samuel F Bunting, Maria Jasin, Bing Xia. Male fertility defect associated with disrupted BRCA1-PALB2 interaction in mice. The Journal of biological chemistry. 2014 Aug 29;289(35):24617-29

Mesh Tags

Substances

PMID: 25016020

search → result