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
References
Afford S, Randhawa S . 2000 Mol. Pathol. 53: 55–63
Blagosklonny MV, An WG, Melillo G, Nguyen P, Trepel JB, Neckers LM . 1999 Oncogene 18: 6460–6468
Bochar DA, Wang L, Beniya H, Kinev A, Xue Y, Lane WS, Wang W, Kashanchi F, Shiekhattar R . 2000 Cell 102: 257–265
Chai YL, Cui J, Shao N, Shyam E, Reddy P, Rao VN . 1999 Oncogene 18: 263–268
Chapman MS, Verma IM . 1996 Nature 382: 678–679
Chen J . 2000 Cancer Res. 60: 5037–5039
Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL, Lee WH . 1996 Cancer Res. 56: 3168–3172
Cortez D, Wang Y, Qin J, Elledge SJ . 1999 Science 286: 1162–1166
D'Amours D, Sallmann FR, Dixit VM, Poirier GG . 2001 J. Cell Sci. 14: 3771–3778
Deng CX, Brodie SG . 2000 Bioessays 22: 728–737
Earnshaw WC, Martins LM, Kaufmann SH . 1999 Annu. Rev. Biochem. 68: 383–424
Fan S, Twu NF, Wang JA, Yuan RQ, Andres J, Goldberg ID, Rosen EM . 1998 Int. J. Cancer 77: 600–609
Ghayur T, Hugunin M, Talanian RV, Ratnofsky S, Quinlan C, Emoto Y, Pandey P, Datta R, Huang Y, Kharbanda S, Allen H, Kamen R, Wong W, Kufe D . 1996 Exp. Med. 184: 2399–2404
Gudas JM, Li T, Nguyen H, Jensen D, Rauscher FJ, Cowan KH . 1996 Cell Growth Differ. 6: 717–723
Gowen LC, Avrutskaya AV, Latour AM, Koller BH, Leadon SA . 1998 Science 281: 1009–1012
Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C, Christians FC, Ellisen LW, Maheswaran S, Oliner JD, Haber DA . 1999 Cell 97: 575–586
Hengartner MO . 2000 Nature 407: 770–776
Jin S, Zhao H, Fan F, Blanck P, Fan W, Colchagie AB, Fornace Jr AJ, Zhan Q . 2000 Oncogene 19: 4050–4057
Jin Y, Xu XL, Yang MC, Wei F, Ayi TC, Bowcock AM, Baer R . 1997 Proc. Natl. Acad. Sci. USA 94: 12075–12080
Kim JW, Kim K, Kang K, Joe CO . 2000 J. Cell Sci. 275: 8121–8125
Larson JS, Tonkinson JL, Lai MT . 1997 Cancer Res. 57: 3351–3355
MacLachlan TK, Somasundaram K, Sgagias M, Shifman Y, Muschel RJ, Cowan KH, El-Deiry WS . 2000 J. Biol. Chem. 275: 2777–2785
Meier P, Finch A, Evan G . 2000 Nature 407: 796–801
Monteiro AN . 2000 Trends Biochem. Sci. 25: 469–474
Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M . 2001 Proc. Natl. Acad. Sci. USA 98: 6086–6091
Rishi AK, Sun RJ, Gao Y, Hsu CK, Gerald TM, Sheikh MS, Dawson MI, Reichert U, Shroot B, Fornace Jr AJ, Brewer G, Fontana JA . 1999 Nucleic Acids Res. 27: 3111–3119
Ruffner H, Verma IM . 1997 Proc. Natl. Acad. Sci. USA 94: 7138–7143
Shao N, Chai YL, Shyam E, Reddy P, Rao VN . 1996 Oncogene 13: 1–7
Sheikh MS, Hollander MC, Fornance Jr AJ . 2000 Biochem. Pharmacol. 59: 43–45
Thomas JE, Smith M, Tonkinson JL, Rubinfeld B, Polakis P . 1997 Cell Growth Differ. 8: 801–809
Thompson CB . 1995 Science 267: 1456–1462
Thangaraju M, Kaufmann SH, Couch FJ . 2000 J. Biol. Chem. 275: 33487–33496
Tournier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ . 2000 Science 288: 870–874
Vijver MJ . 1993 Adv. Cancer Res. 61: 25–56
Walter BN, Huang Z, Jakobi R, Tuazon PT, Alnemri ES, Litwack G, Traugh JA . 1998 J. Biol. Chem. 273: 28733–28739
Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J . 2000 Genes Dev. 14: 927–939
Woo M, Hakem R, Soengas MS, Duncan GS, Shahinian A, Kagi D, Hakem A, McCurrach M, Khoo W, Kaufman SA, Senaldi G, Howard T, Lowe SW, Mak TW . 1998 Genes Dev. 12: 806–819
Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW, Harris CC, Ried T, Deng CX . 1999 Mol. Cell. 3: 389–395
Yuan J, Yankner BA . 1999 Nat. Cell Biol. E44–E45
Yu W . 2000 Breast Cancer Res. 2: 82–85
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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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DOI: https://doi.org/10.1038/sj.onc.1205665
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