Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 35, Pages 24617-24629Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.566141
Keywords
BRCA1; DNA Damage Response; Homologous Recombination; Meiosis; Spermatogenesis; BRCA2; FANCN; Fanconi Anemia; PALB2; Male Infertility
Categories
Funding
- NCI CCSG Grant [P30CA072720]
- Robert Wood Johnson Foundation [67038]
Ask authors/readers for more resources
Background: BRCA1 and PALB2 interact with each other to promote homologous recombination and DNA double strand break repair. Results: Mice with abrogated PALB2-BRCA1 interaction show male fertility defect. Conclusion: PALB2 and BRCA1 function together to ensure normal male meiosis. Significance: This work demonstrates the importance of the PALB2-BRCA1 interaction in vivo and reveals a novel role of PALB2 in sex chromosome synapsis. 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available