BRCA1-BRCT cancer-related point mutations alter sub-cellular localization of BRCA1 in vitro

8^th Euro Global Summit on Cancer Therapy

November 03-05, 2015 Valencia, Spain

Ioannis Drikos, Constantinos E Vorgias and Effrossyni Boutou

National and Kapodistrian University of Athens, Greece

Posters-Accepted Abstracts: J Cancer Sci Ther

Abstract :

Mutations of the breast cancer susceptibility genes brca1 and brca2 account for 30�50% of hereditary breast and ovarian cancer cases reported worldwide. The brca1 gene is the most extensively studied and a large number of mis-sense mutations are located in BRCT tandem repeats of the BRCA1 protein while only few of them are detrimental for the function as well as the interaction of BRCA1 with partner molecules. Mutations at the two C-terminal tandem (BRCT) repeats of BRCA1 detected in breast tumor patients have identified either to lower the stability of the BRCT domain and/or disrupt the interaction of BRCT with synthetic phosphopeptides. Such mutations, especially in the BRCT domain, may also result in the BRCA1 mis-localization due to modifications of BRCA1 binding to interacting proteins. Based on these data we sought to determine whether the M1775K and the V1809F destabilizing mutants of the BRCT domain do alter BRCA1 function in vitro, as shown by cell compartmentalization. The effects of these mutations on sub-cellular localization of BRCA1 protein were studied by following the expression of BRCA1wt and mutants fused to EGFP, in MCF-7 cells. The cytoplasmic mis-localization of M1775K and V1809F mutations which disrupt BRCA1 C-terminal folding, in contrast to the EGFP-BRCA1wt and the less affected variant M1652I, indicate that the functional changes might be crucial for BRCA1 nuclear transport. Additionally, the results compared with computational docking analysis in order to extract more information�s about the impact of the mutation to protein interactions. These data suggest that the impact of the integrity of the BRCA1-BRCT domain in structural level is crucial for proper function of the protein as shown by the modifications in its sub-cellular localization and may contribute to the deficiency of DNA repair procedure and cell cycle control observed in breast cancer cells.

Biography :

Email: johndrikos@yahoo.com