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Dong YS , Hakimi MA , Chen XW , Kumaraswamy E , Cooch NS , Godwin AK , Shiekhattar R
Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair
Molecular Cell. 2003 Nov;12(5) :1087-1099
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We have isolated a holoenzyme complex termed BRCC containing BRCA1, BRCA2, and RAD51. BRCC not only displays increased association with p53 following DNA damage but also ubiquitinates p53 in vitro. BRCC36 and BRCC45 are novel components of the complex with sequence homology to a subunit of the signalosome and proteasome complexes. Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer. In vivo, depletion of BRCC36 and BRCC45 by the small interfering RNAs (siRNAs) resulted in increased sensitivity to ionizing radiation and defects in G2/M checkpoint. BRCC36 shows aberrant expression in sporadic breast tumors. These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.
English Article KeyWords Plus: CANCER SUSCEPTIBILITY GENE; BREAST-CANCER; UBIQUITIN LIGASE; OVARIAN-CANCER; CELL-CYCLE; RADIATION HYPERSENSITIVITY; COP9 SIGNALOSOME; MEIOTIC CELLS; RAD51; DEGRADATION Shiekhattar, R; Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. Research Addresses: Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. *Fox* *Chase* Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. Cited References: BLOOM HJG, 1957, BRIT J CANCER, V11, P359 BOCHAR DA, 2000, CELL, V102, P257 BRZOVIC PS, 2001, NAT STRUCT BIOL, V8, P833 CHAPMAN MS, 1996, NATURE, V382, P678 CHEN A, 2002, J BIOL CHEM, V277, P22085 CHEN JJ, 1998, MOL CELL, V2, P317 CHEN PL, 1998, P NATL ACAD SCI USA, V95, P5287 COPE GA, 2002, SCIENCE, V298, P608 CVETKOVIC D, 2003, CLIN CANCER RES, V9, P1013 DAVIES AA, 2001, MOL CELL, V7, P273 EASTON D, 1993, CANCER SURV, V18, P95 ELSTON CW, 1991, HISTOPATHOLOGY, V19, P403 ETHIER SP, 1993, CANCER RES, V53, P627 FISCH P, 1993, ONCOGENE, V8, P3271 GARCIAHIGUERA I, 2001, MOL CELL, V7, P249 1097-2765