Caspase-3 mediated cleavage of brca1 during uv-induced apoptosis

ABSTRACT The breast cancer suppressor protein, BRCA1 plays an important role in mediating cell cycle arrest, apoptosis and DNA responses to DNA damage signals. In this study, we show that

BRCA1 level is downregulated during UV-induced apoptosis by caspase-3 mediated cleavage. Cleavage of BRCA1 by caspase-3 produced a fragment that contained the C-terminal of the molecule.

Accordingly, treatment of cells with caspase-3 inhibitor or mutation of a specific caspase-3 cleavage site (DLLD) at amino acid 1151–1154 of BRCA1 abolished cleavage and consequential

accumulation of the BRCA1 C-terminal fragment. Whereas expression of the non-cleavable BRCA1 (D/A 1154) mutant conferred the resistance phenotype to UV-induced cell death, expression of the

cleaved BRCA1 C-terminus induced cell death in the absence of UV. Examination of the mechanism of C-terminus-induced cell death revealed that the cleaved fragment triggers the apoptotic

response through activation of BRCA1 downstream effectors, GADD45 and JNK. Altogether, results of our study demonstrate a functional role for caspase-3 mediated cleavage of BRCA1 during

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Biochemistry, University of Pittsburgh, School of Medicine, Pittsburgh, 15261, Pennsylvania, PA, USA Qimin Zhan, Jordan Plisket, Sanjeev Shangary, Abhilasha Rathi & Rajasekaran Baskaran

* Pittsburgh Cancer Institute, University of Pittsburgh, School of Medicine, Pittsburgh, 15261, Pennsylvania, PA, USA Qimin Zhan, Shunqian Jin & Bobby Ng * Department of Biochemistry

and Molecular Biology and the Stanley S. Scott Cancer Center, Louisiana State University, New Orleans, Louisiana, 70112, LA, USA Kevin D Brown Authors * Qimin Zhan View author publications

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Jin, S., Ng, B. _et al._ Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis. _Oncogene_ 21, 5335–5345 (2002). https://doi.org/10.1038/sj.onc.1205665 Download citation *

Received: 18 February 2002 * Revised: 09 May 2002 * Accepted: 14 May 2002 * Published: 02 August 2002 * Issue Date: 08 August 2002 * DOI: https://doi.org/10.1038/sj.onc.1205665 SHARE THIS

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Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * DNA repair * BADD45 * JNK