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  • Review Article
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Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins

Nature Reviews Genetics volume 8, pages 735–748 (2007)Cite this article

Key Points

  • Fanconi anaemia (FA) is a rare genetic disease featuring bone marrow failure, various developmental abnormalities, genomic instability, cancer predisposition and cellular hypersensitivity to DNA-crosslinking drugs. FA has been considered as a useful model to study the pathway that repairs interstrand DNA crosslinks.

  • Three FA genes are identical to breast cancer susceptibility (BRCA) genes. FA and BRCA gene products function in a novel DNA-damage response network.

  • Thirteen FA genes have been identified to date. They can be classified into three groups, each of which acts at a different stage in the FA–BRCA DNA-damage response network.

  • Group I consists of eight FA proteins (FANCA, B, C, E, F, G, L and M). They form the FA core complex, together with FANCA-associated polypeptides FAAP100 and FAAP24. The core complex monoubiquitylates the ID complex in response to DNA damage, and might also participate in DNA repair through the DNA-processing activities of FANCM–FAAP24.

  • Group II consists of FANCD2 and FANCI, which form the FA–ID complex. In response to DNA damage, The ID complex becomes monoubiquitylated, leading to its redistribution to sites of DNA damage where it colocalizes with BRCA1 and γH2AX, a histone H2A variant. These proteins are essential for the redistribution of the ID complex.

  • Group III proteins include FANCD1 (or BRCA2), FANCN(or partner and localizer of BRCA2 (PALB2)), and FANCJ (also known as BRCA1-interacting protein 1 (BRIP1) or BRCA1-associated C-terminal helicase 1 (BACH1)), which are all products of breast cancer susceptibility genes. BRCA2 and PALB2 form a complex with RAD51 recombinase and BRCA1, and this complex mediates homologous recombination-dependent repair of DNA damage. FANCJ is a DNA helicase, which forms a distinct complex with BRCA1, mutL homologue 1(MLH1) and post-meiotic segregation increased 2 (PMS2).

  • FA proteins crosstalk with many molecules that are known to be involved in the DNA-damage response. These include homologous recombination protein RAD51 and translesion polymerases REV1 and REV3. The checkpoint kinase ataxia telangiectasia and Rad3-related protein (ATR) acts upstream of the FA–BRCA network. The Bloom syndrome helicase (BLM) and its partners form a large, stable complex with the FA core complex.

Abstract

Fanconi anaemia (FA) has recently become an attractive model to study breast cancer susceptibility (BRCA) genes, as three FA genes, FANCD1, FANCN and FANCJ, are identical to the BRCA genes BRCA2, PALB2 and BRIP1. Increasing evidence shows that FA proteins function as signal transducers and DNA-processing molecules in a DNA-damage response network. This network consists of many proteins that maintain genome integrity, including ataxia telangiectasia and Rad3 related protein (ATR), Bloom syndrome protein (BLM), and BRCA1. Now that the gene that is defective in the thirteenth and last assigned FA complementation group (FANCI) has been identified, I discuss what is known about FA proteins and their interactive network, and what remains to be discovered.

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Figure 1: The Fanconi anaemia core complex and the Bloom syndrome protein (BLM) complex associate in a supercomplex, BRAFT.
Figure 2: Classification and domain structures of Fanconi anaemia (FA) proteins.
Figure 3: Signalling through the Fanconi anaemia (FA)–breast cancer susceptibility (BRCA) network in response to DNA damage.
Figure 4: Fanconi anaemia (FA) proteins FANCM and FAAP24 form a heterodimer that belongs to the endonuclease family of XPF–ERCC1 and MUS81–EME1.
Figure 5: The Fanconi anaemia (FA)–ID complex may promote translesion bypass through a mechanism similar to that of proliferating cell nuclear antigen (PCNA).
Figure 6: A model for the participation of Fanconi anaemia (FA) proteins in crosslinked DNA-damage repair.

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Acknowledgements

I regret that all of the relevant work and references could not be included owing to space limitations. The highlighted references are for the reader's convenience only, and are by no means the most important. I thank H. Joenje, J. de Winter, L. Li, A. Ruhikanta Meetei, M. Hoatlin, D. Schlessinger and the anonymous reviewers for critical reading of the manuscript and helpful suggestions. The work of my group has been supported in part by the intramural programme of the US National Institutes of Health, National Institute on Aging and the Fanconi Anaemia Research Fund.

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  1. Laboratory of Genetics, National Institute on Aging, National Institutes of Health, 333 Cassell drive, Baltimore, 21093, Maryland, USA

    Weidong Wang

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DATABASES

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Bloom syndrome

breast cancer

Fanconi anaemia

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Glossary

Nucleotide excision repair

A pathway that repairs damaged nucleotides by excising the damaged DNA strand and using the intact complementary strand as the template to repair the damaged strand.

Homologous recombination repair

An error-free pathway that uses homologous sequences in the undamaged chromosome to repair broken DNA ends. The exchange (recombination) between the template and the broken DNA allows restoration of two intact DNA molecules.

Translesion synthesis

An error-prone pathway used by the DNA replication machinery to bypass the damaged DNA without repairing the lesion. The process involves participation of the translesion polymerases, which have low fidelity but can pass through the damaged site.

DNA interstrand crosslinks

A type of DNA damage in which both strands of DNA are covalently linked by a chemical mutagen. This type of linkage can prevent the separation of the two strands, which is a required step during replication and transcription.

Complementation groups

The subclassification of FA patients on the basis of somatic cell hybrid analysis or mutation analysis. Each group of patients has mutations in the same gene.

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Wang, W. Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nat Rev Genet 8, 735–748 (2007). https://doi.org/10.1038/nrg2159

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