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Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis

Oncogene volume 21, pages 5335–5345 (2002)Cite this article

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 UV-induced apoptosis.

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Abbreviations

UV:

Ultraviolet

DSB:

Double strand break

FACS:

fluorescence-activated cell sorting

PI:

propidium iodide

PAGE:

polyacrylamide gel electrophoresis

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Authors and Affiliations

  1. Department of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, Pittsburgh, 15261, Pennsylvania, PA, USA

    Qimin Zhan, Jordan Plisket, Sanjeev Shangary, Abhilasha Rathi & Rajasekaran Baskaran

  2. Pittsburgh Cancer Institute, University of Pittsburgh, School of Medicine, Pittsburgh, 15261, Pennsylvania, PA, USA

    Qimin Zhan, Shunqian Jin & Bobby Ng

  3. 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

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  1. Qimin Zhan
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  2. Shunqian Jin
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  4. Jordan Plisket
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  5. Sanjeev Shangary
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  8. Rajasekaran Baskaran
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Correspondence to Rajasekaran Baskaran.

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Zhan, Q., 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

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