Male Fertility Defect Associated with Disrupted BRCA1-PALB2 Interaction in Mice
| Autor: | Srilatha Simhadri, Samuel F. Bunting, Shoreh Miller, Shridar Ganesan, Yanying Huo, Bing Xia, Shaun E. Peterson, Mantu Bhaumik, Thomas Ludwig, Dharm S Patel, Maria Jasin, Christian Bowman-Colin, Hong Cai |
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| Rok vydání: | 2014 |
| Předmět: |
Male
endocrine system diseases DNA Repair PALB2 Molecular Sequence Data Mutant Biology Biochemistry Mice Meiosis Fanconi anemia In Situ Nick-End Labeling medicine Homologous chromosome Animals Humans Amino Acid Sequence Homologous Recombination skin and connective tissue diseases Molecular Biology Infertility Male Sequence Homology Amino Acid BRCA1 Protein Tumor Suppressor Proteins Synapsis Molecular Bases of Disease Cell Biology medicine.disease Molecular biology medicine.anatomical_structure Fanconi Anemia Complementation Group N Protein Homologous recombination Germ cell DNA Damage |
| Zdroj: | Journal of Biological Chemistry. 289:24617-24629 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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