Expression of human BRCA1δ17-19 alternative splicing variant with a truncated BRCT domain inMCF-7 cells results in impaired assembly of DNA repair complexes and aberrant DNA damageresponse
| Autoři | |
|---|---|
| Rok publikování | 2013 |
| Druh | Článek v odborném periodiku |
| Časopis / Zdroj | Cellular Signalling |
| Citace | |
| Doi | http://dx.doi.org/10.1016/j.cellsig.2013.02.008 |
| Popis | Alternative pre-mRNA splicing is a fundamental post-transcriptional regulatory mechanism. Cancer-specific misregulation of the splicing process may lead to formation of irregular alternative splicing variants (ASVs) with a potentially negative impact on cellular homeostasis. Alternative splicing of BRCA1 pre-mRNA can give rise to BRCA1 protein isoforms that possess dramatically altered biological activities compared with full-length wild-type BRCA1. During the screening of high-risk breast cancer (BC) families we ascertained numerous BRCA1 ASVs, however, their clinical significance for BC development is largely unknown. In this study, we examined the influence of the BRCA1?17-19 ASV, which lacks a portion of the BRCT domain, on DNA repair capacity using human MCF-7 BC cell clones with stably modified BRCA1 expression. Our results show that overexpression of BRCA1?17-19 impairs homologous recombination repair (sensitizes cells to mitomycin C), delays repair of ionizing radiation-induced DNA damage and dynamics of the ionizing radiation-induced foci (IRIF) formation, and undermines also the non-homologous end joining repair (NHEJ) activity. Mechanistically, BRCA1?17-19 cannot interact with the partner proteins Abraxas and CtIP, thus preventing interactions known to be critical for processing of DNA lesions. We propose that the observed inability of BRCA1?17-19 to functionally replace wtBRCA1 in repair of DNA double-strand breaks (DDSB) reflects impaired capacity to form the BRCA1-A and -C repair complexes. Our findings indicate that expression of BRCA1?17-19 may negatively influence genome stability by reducing the DDSB repair velocity, thereby contributing to enhanced probability of cancer development in the affected families. |
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