BRCA1 and its toolbox for the maintenance of genome integrity

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Key Points

  • The breast and ovarian cancer susceptibility type 1 protein (BRCA1) exists as a heterodimer with BRCA1-associated RING domain protein 1 (BARD1) and forms at least three separate macromolecular protein complexes in vivo through abraxas (also known as CCDC98 and FAM175A), BRCA1-interacting protein carboxy-terminal helicase 1 (BACH1; also known as FANCJ and BRIP1) and CtBP-interacting protein (CtIP; also known as RBBP8), each of which regulates a specific set of responses following genotoxic stress.

  • BRCA1 promotes optimal homologous recombination (HR)-mediated DNA repair by orchestrating various steps of the reaction: checkpoint activation, DNA end resection and RAD51 assimilation.

  • Partner and localizer of BRCA2 (PALB2; also known as FANCN) bridges the association between BRCA1 and BRCA2 (also known as FANCD1) and links BRCA1 directly to HR-mediated DNA repair.

  • An emerging ubiquitylation-dependent cascade, involving RING finger protein 8 (RNF8)-, RNF168- or ubiquitin-conjugating enzyme 13 (UBC13; also known as UBE2N)-catalysed ubiquitin chains and their recognition by the ubiquitin-interacting motif-containing receptor-associated protein 80 (RAP80; also known as UIMC1), governs BRCA1 localization in the vicinity of double-stranded DNA breaks.

  • BRCA1 seems to participate in a subset of DNA cross link repair pathways in concert with the BRCA-related Fanconi anaemia components, PALB2, BACH1 and BRCA2.

Abstract

The breast and ovarian cancer type 1 susceptibility protein (BRCA1) has pivotal roles in the maintenance of genome stability. Studies support that BRCA1 exerts its tumour suppression function primarily through its involvement in cell cycle checkpoint control and DNA damage repair. In addition, recent proteomic and genetic studies have revealed the presence of distinct BRCA1 complexes in vivo, each of which governs a specific cellular response to DNA damage. Thus, BRCA1 is emerging as the master regulator of the genome through its ability to execute and coordinate various aspects of the DNA damage response.

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Figure 1: BRCA1 domain organization and interaction partners.
Figure 2: BRCA1 participates in DNA damage signalling.
Figure 3: The connection between the Fanconi anaemia pathway and the BRCA1-linked homologous recombination repair pathway.

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Acknowledgements

This work was supported in part by grants from the National Institutes of Health (CA089239, CA092312 and CA100109 to J.C.), the Startup Fund (Department of Anatomy, The University of Hong Kong to M.S.Y.H.) and Seed Funding for Basic Research (The University of Hong Kong to M.S.Y.H.). J.C is a recipient of an Era of Hope Scholar award from the Department of Defence and a member of the Mayo Clinic Breast SPORE program (P50 CA116201).

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Correspondence to Junjie Chen.

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Glossary

E3 ubiquitin ligase

A protein or protein complex that covalently attaches ubiquitin moieties to its target protein by an isopeptide bond. E3 ubiquitin ligases usually provide the substrate specificity for a ubiquitylation reaction that involves an E1 ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme. Two major classes of E3 ubiquitin ligases have been defined based on their conserved HECT and RING domains.

Homologous recombination

A DNA recombination pathway, which includes the repair of dsDNA breaks, that uses a homologous dsDNA molecule as a template for the repair of the broken DNA.

E2 ubiquitin-conjugating enzyme

A protein that transfers the activated ubiquitin from the E1 ubiquitin-activating enzyme to an E3 ubiquitin ligase. E2 ubiquitin-conjugating enzymes determine ubiquitin chain specificities, and each E2 enzyme associates with several E3 ligases.

Coiled-coil domain

A structural element that is important for mediating protein–protein interactions. The sequence of coiled-coil domains contains repetitive elements of seven apolar residues that form a heptad.

Non-canonical ubiquitin chain

A diubiquitin or polyubiquitin chain comprising ubiquitin molecules that are conjugated by their Lys residues, other than Lys48. Some of these chains do not target proteins for proteosomal degradation.

G2–M checkpoint

A DNA damage-induced transient cell cycle arrest at the G2–M border, usually associated with CHK1 phosphorylation and activation.

Proteasome

A large protein complex that is responsible for breaking down polyubiquitylated proteins.

G1–S checkpoint

A checkpoint that ensures growing conditions are optimal before cells are committed to one round of DNA replication and cell division.

Intra-S phase checkpoint

ATM- and ATR-dependent transient inhibition of DNA replication in response to DNA damage. Defects in an ionising radiation-induced intra-S phase checkpoint cause radioresistant DNA synthesis.

DEAH helicase family

A family of proteins that use ATP and unwind nucleic acids, which have a conserved DEAH box.

Radial chromosome

An abnormal chromosome structure that results from pairing of homologous or non-homologous metaphase chromosomes. These structures are observed in chromosome spreads prepared from cells with an underlying chromosome instability, such as cells from patients with Fanconi anaemia, Bloom syndrome and ataxia telangiectasia.

Gene conversion

A non-reciprocal recombination process that results in an alteration of the sequence of a gene to that of its homologue.

Isogenic

Here, refers to a genotype that has been engineered to be identical to another genotype, with the exception of one or more mutations of interest.

DNA decatenation

An ATP-dependent process for the resolution of replicated sister chromatids that requires topoisomerase II activity.

Chromatid exchange

The physical exchange of genetic material between identical sister chromatids. This process can be enhanced by treatment with DNA damaging agents, such as the cross-linking agent mitomycin C.

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Huen, M., Sy, S. & Chen, J. BRCA1 and its toolbox for the maintenance of genome integrity. Nat Rev Mol Cell Biol 11, 138–148 (2010) doi:10.1038/nrm2831

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