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BRCA1 Protein Structure

Image courtesy of Protein Data Bank http://www.rcsb.org/pdb/


In 1994, the BReast-CAncer susceptibility gene, BRCA1, was identified by positional cloning; subsequently, this tumor supressor gene has been the subject of intensive research effort (Miki et al., 1994). BRCA1 is composed of 22 coding exons distributed over 100 kb of genomic DNA, this gene encodes for an 1863-residue protein (NCBI amino acid sequence) involved in gene regulation and repair processes following DNA damage (Tavtigan et al., 1998). More than 200 different germline mutations associated with cancer susceptibility have been identified. Many disease-predisposing alleles of BRCA1 have loss-of function mutations, the majority of which result in premature truncation of the protein (Tavtigan et al.,1998). Because only 45% of familial breast cancers showed evidence of linkage to BRCA1, the search for a second breast cancer susceptibility gene continued, and in 1995, the BRCA2 gene was identified at chromosome 13q12.36, (Fig.1). Mutations in BRCA1 and BRCA2 are also associated with an increased susceptibility to ovarian, pancreatic, and prostate cancers (Venkitaraman, 2002).

Figure 1. Features of the Human BRCA ProteinsBRCA1 contains an N-terminal RING domain, nuclear localization signals (NLSs), and two C-terminal BRCT domains of ~110 residues (also found in several proteins with functions in DNA repair or cell cycle control). Interacting proteins discussed in the text are shown below approximate regions of binding. BRCA2 contains eight repeats of the ~40 residue BRC motifs. Six of the eight motifs in human BRCA2 can bind directly to RAD51 when expressed in vitro (Image Permit Pending Venkitaranam, 2002 )


Functions of the BRCA1 protein

BRCA1 and BRCA2 exhibit similar patterns of expression and sub-cellular localization. They are both expressed in many tissues in a cell-cycle-dependent manner, their levels are highest during S phase, which is suggestive of functions during DNA replication. Both are localized to the nucleus in somatic cells, where they co-exist in characteristic sub-nuclear foci that redistribute following DNA damage (Venkitaraman, 2001). Current analyses of the protein encoded by BRCA1 seem to be consistent with 2 functions: a role in DNA recombination and/or repair and a role in transcriptional regulation.

Role in DNA repair

Initial evidence suggesting a role of BRCA1 in the repair of damaged DNA was derived from the observation that BRCA1 is hyperphosphorylated in response to DNA damage and relocated to sites of replication forks marked by proliferating cell nuclear antigen (PCNA) . It is likely, therefore, that BRCA1 is phosphorylated at multiple residues by different kinases after DNA damage (Table 1.). However, how each type of phosphorylation affects the functions of BRCA1 remains o bscure (Scully et. al., 1997) .

Phosphorylating Enzyme
Phosphorylation target
Ataxia-telangiectasia mutated (ATM
ATM-related kinase (ATR).
G2/M control kinase, CHK2,

Table 1. The table above shows in colum 1 three different kinases and their amino acid targets in the BERCA1 protein sequence. NOTE: The information presented in the table above comes from (Scully et. al., 1997).

Studies demonstrated that BRCA1 and BRCA2 were involved in protein complexes that activate the repair of DNA doublestranded breaks (DSBs) and initiate homologous recombination (HR), maintaining tumor suppression roles (Venkitaraman, 2001).

Role in transcriptional response to DNA damage

 Based in several studies, it is believed that BRCA1 is involved in the transcriptional regulation of several genes activated in response to DNA damage (Fig. 2) . Such genes include those encoding the p21 CIP1 cyclin-dependent kinase inhibitor, and the GADD45 tumour suppressor (Venkitaraman, 2001 and 2002 ). Evidence of this is that the C-terminus of BRCA1 (amino acids 1528– 1863) binds and activates the basal transcription machinery. Studies demonstrated that the C-terminus of human BRCA1 complexes with RNA polymerase II through RNA helicase A. This interaction appears to involve several proteins associated with the core polymerase complex ( Scully et. al., 1997) .


Fig 2. Protein partners of BRCA1 in DNA damage responses. There is accumulating evidence that BRCA1 performs multiple functions in the cellular response to DNA damage through its interactions with different protein partners. The list of BRCA1-interacting proteins indicated here is not exhaustive but illustrates points made in the text (Image Permit Pending Venkitaraman,2001 ).





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