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Articles

Mislocalization of BRCA1-complex due to ABRAXAS Arg361Gln mutation

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Pages 1291-1301 | Received 10 Mar 2014, Accepted 14 Jul 2014, Published online: 08 Aug 2014
 

Abstract

ABRAXAS is an integral member of BRCA1-complex, which helps in its recruitment to the DNA damage site. It interacts with BRCA1 via its C-terminal phospho-peptide binding motif while the N-terminal associates with RAP80, and thereby recruits the BRCA1-complex at the site of DNA damage. Nonetheless, how ABRAXAS helps in the structural integrity of BRCA1-complex, and its DNA repair mechanism remains elusive. To elucidate the role of ABRAXAS in the DNA repair process, we characterized the ABRAXAS wild type and Arg361Gln mutant using in silico and in vitro approach. It has been observed that ABRAXAS Arg361Gln mutant is responsible for defective nuclear localization of BRCA1-complex, and hence important for DNA repair function. We found conformational changes in ABRAXAS mutant, which impaired binding to RAP80 and further disturb BRCA1-complex localization. The results presented in this paper will help to understand the cause of BRCA1 mislocalization, and various DNA repair defects that occur due to substitution. Comparative study of ABRAXAS wild type and mutant will provide helpful perspective for inhibitor designing that can potentially recompense the deleterious effect(s) of Arg361Gln mutation, and have therapeutic application.

Acknowledgements

We thank DBT-BTIS facility at ACTREC for providing necessary software to this study. Mr Vikrant thanks CSIR for fellowship (09/513 (0072)/2008-EMR-I).

Additional information

Funding

Funding. Funding for this study was supported by DBT [grant number BT/PR10765/BRB/664/2008], [grant number BT/PR12565/BID/07/303/2009]; Seed in Air grant from TMC.

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