Association of BRCA1 with the hRad50-hMre11-p95 Complex and the DNA Damage Response

Abstract

BRCA1 encodes a tumor suppressor that is mutated in familial breast and ovarian cancers. Here, it is shown that BRCA1 interacts in vitro and in vivo with hRad50, which forms a complex with hMre11 and p95/nibrin. Upon irradiation, BRCA1 was detected in discrete foci in the nucleus, which colocalize with hRad50. Formation of irradiation-induced foci positive for BRCA1, hRad50, hMre11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wild-type BRCA1. Ectopic expression of wild-type, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent, methyl methanesulfonate. These data suggest that BRCA1 is important for the cellular responses to DNA damage that are mediated by the hRad50-hMre11-p95 complex.

E2F6 negatively regulates ultraviolet-induced apoptosis via modulation of BRCA1

“…29 The known functions of BRCA1 occur mostly in the nucleus. 24 The molecule becomes localized as discrete nuclear dots during cellular DNA replication (S-phase) and, after DNA damage, nuclear BRCA1 becomes re-distributed into more numerous, smaller foci that co-stain with many proteins associated with DNA repair and replication, for example, Rad51, 22 Rad50/ hMre11/p95, 30 and proliferating cell nuclear antigen. 23 With transient overexpression of E2F6, we demonstrated that E2F6 increases UV-induced BRCA1 nuclear foci and that this effect is related to their association through the C-terminal domain of E2F6.…”

BRCA1 gene in breast cancer

“…Various classes of proteins interact with BRCA1, including: (1) components of the basal transcription machinery [e.g., RNA helicase A and RNA pol II (Anderson et al, 1998;Schlegel et al, 2000a)]; (2) generalized transcriptional coactivators [p300, CBP, Brg1 (Bochar et al, 2000;Pao et al, 2000)] and corepressors [e.g., RbAp46, RbAp48, histone deacetylases-1,2, and CtIP (Yarden and Brody, 1998;Yu et al, 1998)]; (3) tumor suppressors [e.g., p53, RB1, BRCA2 (Chen et al, 1998;Ouichi et al, 1998;Yarden and Brody, 1998;Zhang et al, 1998;Aprelikova et al, 1999;Chai et al, 1999;Fan et al, 2001c)]; (4) steroid hormone receptors, estrogen receptor-a, and androgen receptor (Yeh et al, 2000;Fan et al, 2001a); (5) DNA repair proteins [e.g., Rad51, Rad50, hMSH2 (Scully et al, 1997b;Zhong et al, 1999;Wang et al, 2001a)]; (6) other sequence-specific transcription factors [e.g., c-Myc, Oct-1, and NF-YA Fan et al, 2002b)]; and (7) cell cycle regulatory proteins [e.g., BARD1, E2F1, cyclins (Wu et al, 1996;Wang et al, 1997)]. These interactions are summarized in Figure 1; and the significance of these interactions is discussed in ''Functional Activities of BRCA1''.…”

“…However, another study challenged the view that phosphorylated CtIP dissociates from BRCA1 as a mechanism of BRCA1 induction of DNA damage response genes (Wu-Baer and Baer, 2001). Recent studies suggest that in response to double-strand DNA breaks (DSBs) induced by IR, BRCA1 translocates to subnuclear foci (''dots'') containing Mre11, hRad50, and p95NBS1 (Niejemen breakage syndrome protein) (Zhong et al, 1999;Wu et al, 2000), an enzyme complex implicated in DSB repair. BRCA1 can bind directly to DNA, particularly to branched DNA structures, where it inhibits the nucleolytic activity of the Mre11-hRad50-p95NBS1 (Paull et al, 2001).…”

Increased level of chromosomal damage after irradiation of lymphocytes from BRCA1 mutation carriers

“…BRCA1 is a target for phosphorylation by ATM, ATR and Chk2 triggered by DNA damage and is required for cell cycle checkpoint activation (Shiloh, 2003). BRCA1 interacts with the MRE11-Rad50-NBS1 complex (Zhong et al, 1999), which is involved in the homologous recombination pathway of DSB DNA repair. A role for BRCA1 in chromatin remodelling and activation of transcription have also been described (Bochar et al, 2000).…”