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Review
. 2011 Dec 23;12(1):68-78.
doi: 10.1038/nrc3181.

BRCA1 and BRCA2: different roles in a common pathway of genome protection

Rohini Roy  1 , Jarin Chun, Simon N Powell
Affiliations
Review

BRCA1 and BRCA2: different roles in a common pathway of genome protection

Rohini Roy et al. Nat Rev Cancer. .

Abstract

The proteins encoded by the two major breast cancer susceptibility genes, BRCA1 and BRCA2, work in a common pathway of genome protection. However, the two proteins work at different stages in the DNA damage response (DDR) and in DNA repair. BRCA1 is a pleiotropic DDR protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous recombination. The links between the two proteins are not well understood, but they must exist to explain the marked similarity of human cancer susceptibility that arises with germline mutations in these genes. As discussed here, the proteins work in concert to protect the genome from double-strand DNA damage during DNA replication.

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Conflict of interest statement

Competing interests statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Molecular mechanisms of the DNA damage response
In response to DNA double-strand breaks (DSBs) or replication fork collapse (not shown), sensors (light blue) detect the damage, and signalling mediators recruit or activate effectors that repair the damage and activate cell cycle checkpoints. BRCA1-containing macro-complexes (dark blue) are crucial mediators of the DNA damage response. The BRCA1–abraxas–RAP80 complex associates with ubiquitylated histones near the sites of DNA damage; this is dependent on phosphorylation of histone H2AX (γH2AX), mediator of DNA damage checkpoint protein 1 (MDC1) and RING finger protein 8 (RNF8). The BRCA1–CtBP-interacting protein (CtIP) complex associates with the MRN complex (which is comprised of MRE11, RAD50 and Nijmegen breakage syndrome protein 1 (NBS1)), which senses DSBs and is responsible for DSB resection. The BRCA1–partner and localizer of BRCA2 (PALB2)–BRCA2 complex is important in mediating RAD51-dependent homologous recombination (HR). CHK2-dependent phosphorylation of S988 in BRCA1 appears to be required for the BRCA1–PALB2–BRCA2 effector complex, which is important in RAD51-mediated HR. The BRCA1–BRCA1-interacting protein C-terminal helicase 1 (BRIP1)–DNA topoisomerase 2-binding protein 1 (TOPBP1) complex is associated with DNA repair during replication and may help mediate ataxia telangiectasia and Rad3-related (ATR)–CHK1 signalling, but its precise function is unknown. DNA damage is also recognized by ataxia-telangiectasia mutated (ATM) and ATR kinases, which phosphorylate BRCA1, BRCA1-associated proteins and p53 and mediate signalling to form macro-complexes and activate cell cycle checkpoints.
Figure 2
Figure 2. BRCA1 and BRCA2 functional domains
a | The BRCA1 amino terminus contains a RING domain that associates with BRCA1-associated RING domain protein 1 (BARD1) and a nuclear localization sequence (NLS). The central region of BRCA1 contains a CHK2 phosphorylation site on S988 (REF. 25). The carboxyl terminus of BRCA1 contains: a coiled-coil domain that associates with partner and localizer of BRCA2 (PALB2); a SQ/TQ cluster domain (SCD) that contains approximately ten potential ataxia-telangiectasia mutated (ATM) phosphorylation sites and spans amino acid residues 1280–1524; and a BRCT domain that binds ATM-phosphorylated abraxas, CtBP-interacting protein (CtIP) and BRCA1-interacting protein C-terminal helicase 1 (BRIP1). The BRCA1–abraxas complex is associated with BRCA1 recruitment to sites of DNA damage,,,. The BRCA1–BRIP1 complex, which also contains DNA topoisomerase 2-binding protein 1 (TOPBP1), is associated with DNA repair during replication. The BRCA1–CtIP complex promotes ataxia-telangiectasia and Rad3-related (ATR) activation and homologous recombination (HR) by associating with the MRN complex (which is comprised of MRE11, RAD50 and Nijmegen breakage syndrome protein 1 (NBS1)) and facilitating DNA double-strand break resection. The central region of BRCA1, which contains the SCD, is phosphorylated by ATM. This phosphorylation is important for BRCA1-mediated G2/M and S-phase checkpoint activation, as expression of a BRCA1 mutant that lacks three of the phosphorylation sites (S1387, S1423 and S1524) fails to rescue defective checkpoint activation and ionizing radiation hypersensitivity in a BRCA1-deficient cell line,. b | The N terminus of BRCA2 binds PALB2 at amino acids 21–39 (REF. 68). BRCA2 contains eight BRC repeats between amino acid residues 1009 and 2083 that bind RAD51. The BRCA2 DNA-binding domain contains a helical domain (H), three oligonucleotide binding (OB) folds and a tower domain (T), which may facilitate BRCA2 binding to both single-stranded DNA and double-stranded DNA. This region also associates with deleted in split-hand/split-foot syndrome (DSS1),,. The C terminus of BRCA2 contains an NLS and a cyclin-dependent kinase (CDK) phosphorylation site at S3291 that also binds RAD51 (REF. 53).
Figure 3
Figure 3. Homologous recombination at different types of DNA damage
Exogenous agents produce DNA double-strand breaks (DSBs) with two ends (a), whereas during replication, blocking lesions on the template strand can produce either one-ended DSBs (b) or daughter-strand gaps (DSGs) (c), both of which are preferentially repaired in the S and G2 phases of the cell cycle by the BRCA1–BRCA2-mediated homologous recombination (HR) pathway. During replication, template strand lesions may be repaired either behind the fork or at the fork. Gaps associated with lesions on the parental strand behind the fork cannot be removed by base excision repair (BER) because an undamaged template is needed for repair; therefore, HR is the only available pathway for the repair of DSGs. Cells lacking functional BRCA1 or BRCA2 exhibit an abundance of chromatid breaks, which indicates an attempt to repair DSGs in the absence of a functional BRCA-mediated HR pathway. DSBs that remain unrepaired behind a replication fork can also produce chromatid breaks or aberrant junctions or exchanges. Hence, BRCA1 and BRCA2 have crucial roles in the repair of replication-associated lesions at or behind the replication fork. NHEJ, non-homologous end-joining.
Figure 4
Figure 4. BRCA-deficient cells accumulate chromatid breaks and chromatid exchanges
In the absence of BRCA1 or BRCA2 function, chromatid breaks accumulate, resulting in aberrant chromatid exchanges or other processes involving illegitimate end-joining. If two chromatid breaks are joined to produce a chromosome structure containing two centromeres, a dicentric quadri-radial chromosome is formed, which leads to cell death at mitosis. If an exchange is made with a chromatid fragment without a centromere, processing and cell division can produce a viable cell with a translocation. All of the hallmarks of BRCA-deficient cancers can be explained by the production of chromatid breaks and illegitimate end-joining. Without exchange events between different chromosomes, interstitial deletions, terminal deletions and insertions of chromosome fragments can originate from the chromatid break. In the absence of homologous recombination, the resulting phenotypes can be seen either by spectral karyotyping or by array-comparative genomic hybridization (aCGH), which detects large losses and gains across the genome.
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