Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis.
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.
Zhan
Qimin
Q
Department of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, PA 15261, USA.
Jin
Shunqian
S
Ng
Bobby
B
Plisket
Jordan
J
Shangary
Sanjeev
S
Rathi
Abhilasha
A
Brown
Kevin D
KD
Baskaran
Rajasekaran
R
D017209:Apoptosis / Q000528:radiation effects*; D019313:BRCA1 Protein / Q000378:metabolism*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D017931:DNA Primers / Q000737:chemistry; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology / Q000528:radiation effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D010957:Plasmids; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014466:Ultraviolet Rays; D000097642:GADD45 Proteins
D019313:BRCA1 Protein; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases; D017931:DNA Primers; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D011506:Proteins; D000097642:GADD45 Proteins; C505407:CASP3 protein, human