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Caspase-3 Mediated Cleavage of BRCA1 During UV-Induced Apoptosis

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Caspase-3 Mediated Cleavage of BRCA1 During UV-Induced Apoptosis Oncogene (2002) 21, 5335 – 5345 ª 2002 Nature Publishing Group All rights reserved 0950 – 9232/02 $25.00 www.nature.com/onc Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis Qimin Zhan1,2, Shunqian Jin2, Bobby Ng2, Jordan Plisket1, Sanjeev Shangary1, Abhilasha Rathi1, Kevin D Brown3 and Rajasekaran Baskaran*,1 1Department of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, PA 15261, USA; 2Pittsburgh Cancer Institute, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, PA 15261, USA; 3Department of Biochemistry and Molecular Biology and the Stanley S. Scott Cancer Center, Louisiana State University, New Orleans, Louisiana, LA 70112, USA The breast cancer suppressor protein, BRCA1 plays an have shown that, irrespective of the origin and the important role in mediating cell cycle arrest, apoptosis pathways that activate it, apoptosis proceeds through a and DNA responses to DNA damage signals. In this common mechanism involving predictable, reproduci- study, we show that BRCA1 level is downregulated ble sequence of events that includes DNA during UV-induced apoptosis by caspase-3 mediated fragmentation, chromatin condensation, membrane cleavage. Cleavage of BRCA1 by caspase-3 produced a blebbing, cell shrinkage and disassembly into fragment that contained the C-terminal of the molecule. membrane-enclosed vesicles (Hengartner, 2000). Accordingly, treatment of cells with caspase-3 inhibitor Central components of the apoptotic machinery are or mutation of a specific caspase-3 cleavage site (DLLD) a family of cysteine-proteases termed caspases. at amino acid 1151 – 1154 of BRCA1 abolished cleavage Caspases dismantle the cell by targeting a panoply of and consequential accumulation of the BRCA1 C- proteins for limited proteolysis (Earnshaw et al., 1999). terminal fragment. Whereas expression of the non- Generally synthesized as an inactive proform, they are cleavable BRCA1 (D/A 1154) mutant conferred the activated by proteolytic cleavage. Out of the 14 resistance phenotype to UV-induced cell death, expres- different caspases that have been identified, caspase-3, sion of the cleaved BRCA1 C-terminus induced cell thus far, remains the most common and important death in the absence of UV. Examination of the effector of apoptotic processes. Observations made in mechanism of C-terminus-induced cell death revealed caspase-3-deficient mice indicate that this protein is that the cleaved fragment triggers the apoptotic response necessary for specific apoptotic processes such as DNA through activation of BRCA1 downstream effectors, degradation, nuclear condensation, plasma membrane GADD45 and JNK. Altogether, results of our study blebbing, and proteolysis of certain substrates (Woo et demonstrate a functional role for caspase-3 mediated al., 1998). Generally, caspase-3 cleavage results in cleavage of BRCA1 during UV-induced apoptosis. functional inactivation of its targets; however, a Oncogene (2002) 21, 5335 – 5345. doi:10.1038/sj.onc. handful of proteins are activated by caspase-3 cleavage. 1205665 For example, Poly ADP-Ribose polymerase-1 (PARP- 1) when proteolyzed by caspase-3 produces a c- Keywords: DNA repair; BADD45; JNK terminal fragment that totally inhibits full-length PARP activity to allow apoptotic advancement (D’Amours et al., 2000; Kim et al., 2000). Similarly, Introduction cleavage of protein kinase C (PKC) d and j generates a 40 kDa catalytically active fragment that when Apoptosis is a normal physiological process that plays overexpressed results in events typical of apoptotic an important role in embryonic development and tissue advance (Ghayur et al., 1996). Thus, caspase-3 homeostasis maintenance (Afford and Randhawa; contributes to apoptotic progression not only through Meier et al., 2000). Because apoptosis is genetically functional inactivation but also through activation of programmed, its deregulation often contributes to target proteins. pathologies such as tumor promotion, immunodefi- The breast cancer suppressor protein, BRCA1 is a ciency diseases, and neurodegenerative disorders multifunctional protein implicated in DNA repair, cell (Thompson, 1995; Yuan and Yankner, 1999). cycle regulation and transcription (Vijver, 1993; Yu, Concerted efforts to characterize the apoptotic process 2000). BRCA1 is a 220 kDa nuclear protein, whose expression and phosphorylation is regulated in a cell cycle-dependent manner (Chen et al., 1996; Gudas et *Correspondence: R Baskaran, Molecular Genetics and Biochem- al., 1996; Ruffner and Verma, 1997). On its N- istry, E1205 Biomedical Science Tower, University of Pittsburgh terminus, BRCA1 contains a cysteine/histidine rich Medical Center, Pittsburgh, Pennsylvania, PA 15261, USA; E-mail: [email protected] RING finger domain that mediates its binding to Received 18 February 2002; revised 9 May 2002; accepted 14 May another RING finger containing protein, termed Bard1 2002 (Jin et al., 1997). The C-terminus of BRCA1 contains a Cleavage of BRCA1 by caspase-3 Q Zhan et al 5336 duplicated globular domain, the BRCT domain, that is A previous study determined that the breast cancer shared in many DNA repair proteins including tumor suppressor protein, BRCA1 level is down- XRCC1, DNA ligase III and IV, and the cell cycle regulated both at mRNA and protein level by UV-C checkpoint protein, Rad9 (Deng and Brodie, 2000). radiation in a dose- and time-dependent manner (Fan Exposure to genotoxic agents such as UV and ionizing et al., 1998). Another study showed that the steady- radiation induces BRCA1 phosphorylation by PI-3 state level of BRCA1 is regulated by proteolysis and kinase related family of kinases, ATM and ATR that N-acetyl-leu-leu-norleucinal (ALLN), an inhibitor (Cortez et al., 1999; Chen, 2000). It is generally of the proteasome caused accumulation of BRCA1 thought that phosphorylation activates its DNA repair protein (Blagosklonny et al., 1999). In this study we capability since mutations of the ATM/ATR phos- show that BRCA1 is cleaved by caspase-3 during UV- phorylation site on BRCA1 abrogates its DNA repair induced apoptosis. Cleavage of BRCA1 by caspase-3 function. A recent study showed that BRCA1 coexists caused accumulation of a C-terminal 90 kDa fragment with a number of DNA repair proteins including the of BRCA1 that when overexpressed induced cell death mismatch repair (MMR) proteins MLH1, MSH6, and in the absence of UV. Correlating well with activation MSH2, the Ataxia telangiectasia mutated (ATM) of cell death response the C-terminus of BRCA1 protein, and the Bloom’s syndrome protein (BLM), in activated GADD45/JNK signaling cascade. Conver- a multiprotein complex termed BASC (BRCA1- sely, expression of a non-cleavable BRCA1 mutant associated genome surveillance complex) (Wang et al., conferred protection against cell death and blocked 2000). Further, cells impaired in BRCA1 function GADD45 and JNK activation by UV radiation. These display impaired transcription-coupled repair (TCR) of results identify a functional role for caspase-mediated oxidative DNA damage arising from IR and H2O2 cleavage of BRCA1 in the regulation of cell death exposure (Gowen et al., 1998). Such findings support a response to UV irradiation. genome protection function for BRCA1 through its DNA repair capability. Results A distinct role for BRCA1 in transcriptional regula- tion has been proposed (Chapman and Verma, 1996; Cleavage of BRCA1 during UV-induced apoptosis Monteiro et al., 2000). The C-terminus of BRCA1, when fused to the GAL4 DNA binding domain activated To assess the temporal effect of genotoxic agent- GAL4 promoter. In transient transfection assays, induced apoptosis on the integrity of BRCA1, HL-60 BRCA1 increased p53-dependent and independent cells (a well-studied model system for apoptosis) were transcription from the p21WAF1/CIP1 and GADD45 induced to undergo apoptosis by exposure to 60 joules/ promoters (Chai et al., 1999; Jin et al., 2000). In m2 of UV-C radiation. Induction of apoptosis was addition, BRCA1 caused accumulation of p53 after evident by the appearance of a detectable population gamma-irradiation through transcriptional stimulation of cells containing sub-2N complement of DNA after of the p53-responsive promoter, MDM2. A number of irradiation (Figure 1a). The time-dependent cleavage of transcription regulatory proteins including ATF1, p53, the apoptotic marker proteins, caspase-3 (Figure 1b) BARD1, CtIP, CBP/p300, and RNA Polymerase II have and poly-ADP-polymerase (PARP) (Figure 1c) further been shown to interact with BRCA1 (Monteiro et al., confirmed apoptotic induction in irradiated cells. 2000). BRCA1 may also regulate transcription through Immunoprecipitation followed by immunoblotting of interaction with the SWI/SNF chromatin-remodeling BRCA1 revealed the presence of a *220 kDa BRCA1 complex (Bochar et al., 2000). band that, following UV-irradiation, displayed retarded A major transcriptional target of BRCA1 is the electrophoretic migration (Figure 1d, compare lanes 1 DNA damage-responsive gene, GADD45. Overexpres- and 2), due to UV-stimulated phosphorylation (Thomas sion of BRCA1 caused transcriptional stimulation of et al., 1997). In addition to full-length BRCA1, an the DNA damage-responsive gene GADD45 (Harkin et immunoreactive band of *90 kDa MW was detected in al., 1999). Studies involving high-density cDNA array UV-irradiated cells but not in control population (lane screening identified many genes, including GADD45,as 2). Concomitant with an increase in the abundance of the BRCA1-regulated
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