Trends in Molecular Medicine
ReviewThe relationship between the roles of BRCA genes in DNA repair and cancer predisposition
Section snippets
BRCA1 and the response to DNA damage
The effective repair of DNA damage requires damage-sensing mechanisms, and then transduction of damage signals to downstream effectors that arrest the cell cycle at checkpoints and repair the damage (Fig. 1) 4., 5.. The related kinases, ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related), are central to the DNA-damage response. Loss of ATM abolishes the checkpoints at the G1–S transition, in S phase and at the G2–M boundary [6]. ATM controls the phosphorylation
The role of BRCA1 in DNA repair by homologous recombination
A direct role for BRCA1 in DNA repair was proposed when it was shown that BRCA1 localizes to subnuclear foci containing RAD51 during the S and G2 phases of the cell cycle [12]. RAD51 is an integral component of a type of DNA-damage repair known as ‘homologous recombination’, which repairs double-strand breaks (DSBs) and interstrand crosslinks [13]. In mitotic cells forced to arrest DNA replication, or damaged by UV light, BRCA1 and RAD51 move from their native foci and relocate to sites of DNA
BRCA1 as a regulator of multiple repair effectors
In addition to its importance in DSB repair, BRCA1 might also play a role in nucleotide-excision repair (NER) [16]. NER can be subdivided into two pathways: transcription-coupled repair (TCR) [17] and global genomic repair (GGR) [16]. TCR is activated when the basal transcriptional machinery is arrested by DNA-base damage. The transcriptional complex must first be removed by components of the TCR machinery before the lesion can be repaired by NER proteins. Although the exact role of BRCA1 in
BRCA1 and chromatin remodelling at sites of DNA damage
Chromatin is remodelled around DSBs, presumably to facilitate repair processes. The C-terminal tail of the histone H2AX becomes phosphorylated within a few minutes of exposure to IR, and this modified form of the protein becomes associated with DSBs, possibly facilitating chromatin remodelling [23]. Following this, BRCA1 and then either RAD50 or RAD51 are recruited to the same sites. H2AX is required for the IR-induced formation of BRCA1, but not RAD51, foci [24]. Whether the phosphorylation of
The role of BRCA2 in DNA repair by homologous recombination
BRCA1 and BRCA2 can interact in vivo but this appears to involve <5% of the cellular pool of either protein [27]. Furthermore, analyses of two distinct BRCA1-associated protein complexes did not detect the presence of BRCA2 9., 25.. Nevertheless, BRCA1 and BRCA2 have been implicated in similar DNA-repair processes. For example, it has been demonstrated that BRCA2 can interact with RAD51 via the BRC repeats and via a C-terminal domain, and this was the first evidence associating BRCA2 in
Fanconi anaemia and BRCA1 and BRCA2
Some unexpected and potentially informative insight into the role of BRCA genes in human DNA repair has come from recent studies of Fanconi anaemia (FA) 48., 49., 50., a complex disorder characterized by congenital abnormalities, progressive bone-marrow failure and cancer susceptibility [51]. Owing to the heterogeneity of disease phenotypes, there is often considerable difficulty in making a firm clinical diagnosis. Therefore, the cellular hypersensitivity to DNA crosslinking agents (such as
Concluding remarks and future prospects
An increased understanding of the roles of BRCA1 and BRCA2 in DNA repair is beginning to suggest potential therapeutic strategies. The requirement for both proteins in DNA repair by gene conversion suggests that, in common with cells deficient in the related FA genes, tumours deficient in BRCA1 or BRCA2 might be highly sensitive to DNA crosslinking agents. The knowledge that other DNA DSB-repair mechanisms, such as NHEJ and SSA, can compensate for a lack of gene conversion in certain
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