Inherited mutations that affect a single allele of either BRCA1 or BRCA2 cause a hereditary breast and ovarian cancer syndrome, which accounts for 30–60% of familial breast cancer cases.
Biallelic germline mutations in BRCA2 are also associated with the very rare D1 complementation group of Fanconi anaemia. The clinical features of FA-D1 patients — who develop Wilms' tumour, breast cancer and medulloblastoma — differ from typical FA cases.
BRCA and FA proteins work in a network of connected biological processes, and not in a linear sequence of events that constitutes a single 'pathway'. One key purpose of the network is to deal with lesions that block DNA replication — such as intra- or inter-strand DNA crosslinks — so preserving chromosome stability during the S and G2 phases of the cell cycle.
When sensed, replication-blocking lesions trigger cell-cycle arrest, which requires DNA-damage-activated checkpoint kinases such as ATM (which is mutated in ataxia telangiectasia) or ATR (which is mutated in Seckel syndrome), as well as BRCA1 and the FA protein FANCD2.
Replication-blocking lesions can be repaired — and replication resumed — through error-free processes that involve homologous recombination or error-prone, mutagenic processes that involve translesion synthesis. BRCA2 and RAD51 work directly to mediate recombination, as might FANCD2, whereas the precise functions of other FA proteins in recombination or translesion synthesis are unclear at present.
Each of the BRCA and FA proteins is likely to have very distinct functions within this network of biological processes. So, the clinical syndromes — including cancers — that are associated with their inactivation could be more mechanistically distinct than is supposed at present, demanding careful consideration of how emerging molecular understanding can best be translated to improve patient care.
Recent evidence connects the proteins that are encoded by the BRCA1 and BRCA2 breast cancer susceptibility genes, and other tumour suppressors — such as the Fanconi anaemia gene products — to cell-cycle checkpoint control and DNA repair by homologous recombination. Do these connections represent a linear biological pathway or do they, instead, reflect a network of processes that prevent aberrations in chromosome structure during the S and G2 phases of the cell cycle? This distinction has important implications for current models to explain the pathogenesis of the cancer susceptibility syndromes that are associated with BRCA or Fanconi anaemia gene mutations.
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I apologize to authors whose papers have not been cited owing to space constraints. I am grateful to K.J. Patel (Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge) for his generous help in formulating ideas concerning connections between the FA proteins and the BRCA network. I owe similar thanks to L. Pellegrini, T. Lo and T. Blundell (Department of Biochemistry, University of Cambridge) and members of my laboratory including D. Yu, M. Lomonosov and M. Sangrithi, for helpful discussions that have helped to refine several points in this paper. Work in my laboratory is supported by the MRC and Cancer Research UK.
The author declares no competing financial interests.
- FANCONI ANAEMIA
A very rare disorder that is characterized by developmental abnormalities in the skeleton, skin pigmentation and other organs, progressive failure of the bone marrow to replenish platelets and red and white blood cells, and susceptibility to acute myeloid leukaemia and squamous-cell carcinomas.
- CELL-CYCLE CHECKPOINTS
Regulatory mechanisms that do not allow the initiation of a new phase of the cell cycle before the previous one has been completed, or that temporarily arrest cell-cycle progression in response to stress. DNA damage activates specific checkpoints at the G1–S and G2–M boundaries, and in S phase, with each one based on a different mechanism.
- SISTER-CHROMATID EXCHANGE
A genetic exchange that occurs between the sister chromatids of mitotic chromosomes. It can be observed after labelling during replication with the pyrimidine analogue bromodeoxyuridine.
- SYNAPTONEMAL COMPLEX
A structure that holds paired chromosomes together during prophase 1 of meiosis and that promotes genetic recombination.
- BRC REPEATS
These recur eight times in human BRCA2 and its mammalian homologues, and at varying frequency in proteins from lower eukaryotes, even though some of these simpler proteins bear little overall similarity to mammalian BRCA2 molecules. The high level of evolutionary conservation indicates an important function for these RAD51-binding peptide motifs.
The gene that encodes this protein (a DNA helicase) is mutated in Bloom syndrome. Individuals with this syndrome have short stature, sun sensitivity, immunodeficiency, decreased fertility and a predisposition to various cancers.
- NON-HOMOLOGOUS END-JOINING
This is an error-prone pathway that quickly seals DNA double-strand breaks at the expense of creating microdeletions. It is the predominant repair mode in mammalian cells and uses the KU70–KU80 heterodimer, which recruits the DNA-PK catalytic subunit. XRCC4–ligase IV finally seals the break.
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Venkitaraman, A. Tracing the network connecting brca and fanconi anaemia proteins. Nat Rev Cancer 4, 266–276 (2004). https://doi.org/10.1038/nrc1321
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