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BRCA1 is a breast and ovarian specific tumor suppressor. Approximately 50% of hereditary breast cancers can be attributed to BRCA1, and women carrying heterozygous mutations in BRCA1 have approximately a 90% lifetime risk of developing cancer.
BRCA1 is a 220-kd primarily nuclear phosphoprotein. Expression of BRCA1 varies with the cell cycle, reaching highest expression in S phase (Chen et al., 1996), during which time it forms nuclear structures visible by immunofluorescence as punctate nuclear foci. Following DNA damage, BRCA1 is dispersed from the S-phase foci and relocalized to damage-induced foci. BRCA1 colocalizes in these damage-induced foci with a number of proteins involved in the DNA damage response (Scully et al., 1997a). The phosphorylated histone H2A.X, which marks tracts of chromatin surrounding damaged DNA, significantly overlaps with BRCA1following DNA damage; thus, BRCA1 damage-induced foci are thought to be sites of DNA repair (Paull et al.,2000).
Most of the cellular pool of BRCA1 exists as a heterodimer with BARD1, suggesting that the functions of the two proteins are tightly linked. Together, BRCA1/BARD1 form an active E3 ubiquitin ligase, and the ubiquitination function of the heterodimer likely plays a large role in BRCA1 tumor suppression. In addition, a body of evidence suggests that the BRCA1/BARD1 heterodimer may play a direct role in DNA repair. Notably, BRCA1/BARD1 interacts directly with aberrant DNA structures (Paull et al., 2001; Simons et al., 2006) as well as with a number of proteins involved in the DNA damage response.
BRCA1 relocalization to damage-induced foci coincides with its phosphorylation (Scully et al., 1997a). BRCA1is phosphorylated by ATM, ATR, and chk2 on several serines throughout the length of the protein in response to DNA damage, suggesting that phosphorylation of BRCA1 plays a role in DNA damage response (Cortez et al.,1999; Gatei et al., 2001; Lee et al., 2000). Sites of phosphorylation on BRCA1 vary with the type of DNA damage, with ATM-sites specific for ionizing radiation and other damaging agents that cause double strand breaks and ATR-sites specific for damage caused by ultraviolet radiation (Gatei et al., 2001). These phosphorylation events appear to have downstream signaling consequences, as certain damage-induced phosphorylation events elicited by ATM first require proper phosphorylation of BRCA1 (Foray et al., 2003).
BRCA1 appears to play a role in two distinct pathways for double strand break repair, non-homologous end joining and homology-directed repair. Non-homologous end joining is an error-prone system for DNA repair that can result in loss of sequence information around the break. Homology-directed repair, in contrast, uses regions of homology to preserve sequence integrity surrounding a double-strand break. Homology directed repair might be as simple as exposing single-stranded DNA on both sides of the break through action of an exonuclease, enabling annealing of exposed complementary sequence. Homology-directed repair may alternatively be more complex, involving homologous recombination proteins in a process that requires resection of single-strands around the break, a search for homologous sequence on an intact molecule, synthesis of new DNA using a homologous sequence as a template, and resolution of the intertwined recombinant DNA strands (Figure 1a). This process results in double-strand break repair with greater fidelity than single-strand annealing or non-homologous end joining. However, the requirement for a homologous template for repair is a limitation of double-strand-break repair by homologous recombination. In mammalian cells, repair by homologous recombination is therefore primarily restricted to late S or G2 phase of the cell cycle, when an identical sister chromatid is available (Rothkamm et al., 2003).
Studies examining the role of BRCA1 in DNA repair have yielded seemingly conflicting results, with BRCA1implicated in both non-homologous end joining and homologous repair. BRCA1 interacts with proteins involved in both the non-homologous end-joining pathway (including the Mre11, Rad50, Nbs1 complex) (Greenberg et al., 2006) and homologous repair (RAD51 and BRCA2, among others) (Chin et al., 1998; Scully et al., 1997b) and forms damage-induced foci irrespective of the cell cycle. In addition, a number of cell-based experiments support involvement of BRCA1 in both pathways. Studies of BRCA1 using a reporter for homology-directed repair have shown that BRCA1 promotes both single-strand annealing and homologous recombination, suggesting that BRCA1 is involved in homology-directed repair upstream of the divergence of SSA and HR (Moynahan et al., 1999; Snouwaert et al., 1999; Stark et al., 2004). On the other hand, extracts from BRCA1-deficient cells are deficient in end-joining (Zhong et al., 2002). Together, these data suggest that BRCA1 is either involved in double strand break repair upstream of both NHEJ and HDR, or BRCA1 functions in a manner common to both types of DNA repair.
BRCA1 has also been linked with a number of other DNA repair processes, including mismatch repair (through interactions with the mismatch repair proteins MSH2, MSH6, and MLH1) and inter-strand crosslink repair (Wang et al., 2000). Intriguingly, there is a growing body of evidence linking BRCA1 with the Fanconi anemia pathway for inter-strand crosslink repair. Fanconi anemia, a disorder characterized by developmental defects, chromosomal abnormalities, and susceptibility to DNA cross-linking agents, is caused by recessive mutations in any one of at least twelve genes. Although BRCA1 does not appear to be a Fanconi protein, several BRCA1interactors are linked to Fanconi anemia, including BRCA2 (FancD1), BACH1 (FancJ), and FancA (Cantor et al., 2001; Chen et al., 1998; Folias et al., 2002).
Because inter-strand crosslinks may be converted to double-strand breaks in the course of repair (Figure 1b) (McHugh et al., 2001; Niedernhofer et al., 2001; Rothfuss and Grompe, 2004), BRCA1 may affect the Fanconi pathway after a partially-repaired DNA is shunted into a homologous recombination pathway. On the other hand, because BRCA1 appears to play a role in repairing a disparate collection of DNA lesions, it is possible that BRCA1 acts in a manner that is upstream of or common to many DNA repair pathways, such as acting as a sensor for DNA damage.