Defects in recombination activity caused by somatic and germline mutations in the multimerization/BRCA2 binding region of human RAD51 protein |
| |
| Institution: | 1. Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT 05405, United States;2. Department of Microbiology & Molecular Genetics, Larner College of Medicine at the University of Vermont, Burlington, VT 05405, United States;3. University of Vermont Cancer Center, Burlington, VT 05405, United States;4. Tumor Microenvironment Laboratory, QIMR Berghofer, Herston Rd., Herston, QLD 4006, Australia;1. Laboratory of Silkworm Science, Kyushu University Graduate School of Bioresource and Bioenvironmental Sciences, 6-10-1 Hakozaki, Fukuoka 812-8581, Japan;2. Insect Growth Regulation Research Unit, National Institute of Agrobiological Sciences, 1-2 Owashi, Tsukuba, Ibaraki 305-8634, Japan;1. Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas;2. Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, China;3. Division of Urology, Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania;1. Division of Pharmaceutical Sciences, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093, United States;2. Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, 92093, United States;1. Laboratory of Evolutionary Genetics, Department of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia;2. Institute for Research and Development of Sustainable Ecosystems, Faculty of Veterinary Medicine, Heinzelova 55, 10000 Zagreb, Croatia |
| |
| Abstract: | The human RAD51 recombinase possesses DNA pairing and strand exchange activities that are essential for the error-free, homology-directed repair of DNA double-strand breaks. The recombination activities of RAD51 are activated upon its assembly into presynaptic filaments on single-stranded DNA at resected DSB ends. Defects in filament assembly caused by mutations in RAD51 or its regulators such as BRCA2 are associated with human cancer. Here we describe two novel RAD51 missense variants located in the multimerization/BRCA2 binding region of RAD51. F86L is a breast tumor-derived somatic variant that affects the interface between adjacent RAD51 protomers in the presynaptic filament. E258A is a germline variant that maps to the interface region between the N-terminal and RecA homology domains of RAD51. Both variants exhibit abnormal biochemistry including altered DNA strand exchange activity. Both variants inhibit the DNA strand exchange activity of wild-type RAD51, suggesting a mechanism for negative dominance. The inhibitory effect of F86L on wild-type RAD51 is surprising since F86L alone exhibits robust DNA strand exchange activity. Our findings indicate that even DNA strand exchange-proficient variants can have negative functional interactions with wild-type RAD51. Thus heterozygous F86L or E258 mutations in RAD51 could promote genomic instability, and thereby contribute to tumor progression. |
| |
| Keywords: | RAD51 Recombination Homology-directed repair Cancer Variant Presynaptic filament |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
