High Levels of Wild-Type BRCA2 Suppress Homologous Recombination
| Autor: | Maureen M. Mundia, Mark D. Baker, Alissa C. Magwood |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Small interfering RNA
endocrine system diseases Mitomycin RAD51 Biology Cell Line Mice Structural Biology Transcriptional regulation Animals Humans RNA Small Interfering Homologous Recombination skin and connective tissue diseases neoplasms Molecular Biology Gene Cell Proliferation BRCA2 Protein Cell Nucleus Hybridomas Wild type Genes p53 Molecular biology female genital diseases and pregnancy complications Gene Expression Regulation Proto-Oncogene Proteins c-bcl-2 Ectopic expression Rad51 Recombinase Homologous recombination Recombination DNA Damage |
| Zdroj: | Journal of Molecular Biology. 421:38-53 |
| ISSN: | 0022-2836 |
| DOI: | 10.1016/j.jmb.2012.05.007 |
| Popis: | Endogenous levels of the BRCA2 (breast cancer susceptibility 2) protein promote homologous recombination by regulating the essential strand exchange protein RAD51. To examine BRCA2 function in homologous recombination, we expressed human BRCA2 in control mouse hybridoma cells, as well as those that were depleted of endogenous Brca2 by small interfering RNA. With moderate human BRCA2 expression, homologous recombination was stimulated. Conversely, a higher level of BRCA2 reduced homologous recombination and DNA-damage-induced Rad51 foci formation. Cells expressing high levels of BRCA2 feature normal growth, increased sensitivity to mitomycin C, and increased illegitimate recombination. BRCA2-overexpressing cells are also characterized by suppression of p53 transcriptional regulation and a corresponding reduction in the expression of the p53-responsive genes Noxa and p21. Notably, in cells expressing high levels of BRCA2, small interfering RNA depletion of human BRCA2 or ectopic expression of Rad51 increases homologous recombination and decreases illegitimate recombination. Thus, high levels of wild-type BRCA2 perturb Rad51-mediated homologous recombination, and relatively normal recombination responses can be restored by rebalancing recombination factors. |
| Databáze: | OpenAIRE |
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