First Author | Simhadri S | Year | 2014 |
Journal | J Biol Chem | Volume | 289 |
Issue | 35 | Pages | 24617-29 |
PubMed ID | 25016020 | Mgi Jnum | J:267154 |
Mgi Id | MGI:6198722 | Doi | 10.1074/jbc.M114.566141 |
Citation | Simhadri S, et al. (2014) Male fertility defect associated with disrupted BRCA1-PALB2 interaction in mice. J Biol Chem 289(35):24617-29 |
abstractText | 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. |