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The Fanconi anaemia pathway: new players and new functions

Key Points

  • The Fanconi anaemia pathway comprises 19 Fanconi anaemia proteins (FANCA to FANCT) and many associated proteins.

  • Germline inactivation of any of the Fanconi anaemia genes causes the disease Fanconi anaemia, which is a genetic disorder characterized by bone marrow failure and predisposition to cancer.

  • The Fanconi anaemia pathway intersects with many other repair processes to respond to interstrand crosslink (ICL) DNA lesions.

  • Studies in the Xenopus egg extract system have provided important insights into the molecular mechanisms of ICL repair through the Fanconi anaemia pathway.

  • Fanconi anaemia proteins have other functions in addition to ICL repair. Fanconi anaemia proteins, notably FANCD2, have crucial roles in replication fork protection and cytokinesis.

  • The Fanconi anaemia pathway, together with other repair processes such as homologous recombination, nucleotide excision repair, translesion synthesis and alternative end joining, forms an intricate network beyond the core ICL repair components to repair diverse DNA lesions.

Abstract

The Fanconi anaemia pathway repairs DNA interstrand crosslinks (ICLs) in the genome. Our understanding of this complex pathway is still evolving, as new components continue to be identified and new biochemical systems are used to elucidate the molecular steps of repair. The Fanconi anaemia pathway uses components of other known DNA repair processes to achieve proper repair of ICLs. Moreover, Fanconi anaemia proteins have functions in genome maintenance beyond their canonical roles of repairing ICLs. Such functions include the stabilization of replication forks and the regulation of cytokinesis. Thus, Fanconi anaemia proteins are emerging as master regulators of genomic integrity that coordinate several repair processes. Here, we summarize our current understanding of the functions of the Fanconi anaemia pathway in ICL repair, together with an overview of its connections with other repair pathways and its emerging roles in genome maintenance.

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Figure 1: Cooperation of Fanconi anaemia, nucleotide excision repair, translesion synthesis and homologous recombination proteins in a common interstrand crosslink repair pathway.
Figure 2: The Fanconi anaemia pathway has a key role in stabilizing stalled replication forks.
Figure 3: Crosstalk between the Fanconi anaemia pathway and other repair processes.

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Acknowledgements

The authors apologize for the many articles that could not be cited owing to space limitations. R.C. is a recipient of the Ovarian Cancer Research Fellowship (OCRF) and Claudia Adams Barr Program. P.S. is a recipient of a Leukaemia and Lymphoma Society (LLS) fellowship. This work was supported by a Stand Up To Cancer (SU2C) – Ovarian Cancer Research Fund-Ovarian Cancer National Alliance-National Ovarian Cancer Coalition Dream Team Translational Research Grant (grant number SU2C-AACR-DT16-15). SU2C is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. This work was also supported by grants from the U.S. National Institutes of Health (R01DK43889, R37HL052725 and P01HL048546), the Breast Cancer Research Foundation and the Fanconi Anaemia Research Fund (to A.D.D.).

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DATABASES

The Fanconi anaemia mutation database

FURTHER INFORMATION

Oregon Health & Science University FA Cell Repository

The Fanconi Anaemia Research Fund

Glossary

Nucleotide excision repair

A DNA repair mechanism that removes bulky DNA lesions induced by ultraviolet light. Germline inactivation of nucleotide excision repair genes results in severe human diseases.

Homologous recombination

A double-strand DNA break repair pathway that functions mainly in the S phase of the cell cycle and uses the sister chromatid as a template to synthesize DNA around the break. This repair process is typically error free.

Translesion synthesis

A DNA damage tolerance pathway that allows replication to bypass DNA lesions and requires switching out regular DNA polymerases for error-prone translesion polymerases. The use of translesion synthesis is thought to introduce DNA mutations throughout the genome.

Fanconi anaemia pathway

A DNA repair pathway that specifically functions in interstrand crosslink (ICL) repair. The Fanconi anaemia pathway also has various roles in addition to ICL repair, such as the stabilization of replication forks. Germline inactivation of any Fanconi anaemia gene causes the Fanconi anaemia disease, which is a cancer predisposition syndrome.

In vitro Xenopus system

An extract from Xenopus laevis frog eggs that can support DNA replication and key genome maintenance processes and is thus used for biochemical studies of these processes.

CMG complex

An 11-member eukaryotic replicative helicase comprising the ring-shaped MCM2–MCM7 hexameric core, and the accessory factors CDC45 and the GINS complex.

Xeroderma pigmentosum

A genetic disorder in which nucleotide excision repair components have been inactivated. It is characterized by a defect in repairing damage caused by ultraviolet light; as a consequence, patients with xeroderma pigmentosum are extremely sensitive to ultraviolet light and are highly predisposed to skin malignancies.

Poly(ADP-ribose) polymerase inhibitor

(PARPi). A novel class of agents that exhibit anticancer activity by inhibiting the PARP family of enzymes. As tumours with inactivated homologous recombination are extremely sensitive to PARPi, their use has recently been approved for the treatment of cancers with mutations in the breast cancer susceptibility genes BRCA1 or BRCA2.

Replication stress

Perturbations originating from endogenous or exogenous sources that can affect the proper progression and completion of DNA replication.

Dormant origins

Origins of replication that are kept silent by the checkpoint response but become necessary for the completion of DNA replication when replication fork progression is inhibited.

Under-replicated DNA

Slower or incomplete replication of certain chromosome regions. Under-replication can be the consequence of replicative stress and can generate ultra-fine DNA bridges and genomic instability.

Alternative end joining

A double-strand DNA break (DSB) repair pathway that requires microhomology around the break to process the lesion. This pathway can compensate for the loss of homologous recombination or functions as the backup pathway to non-homologous end joining for the joining of DSBs in the context of V(D)J recombination. Alternative end joining is highly mutagenic.

Non-homologous end joining

(NHEJ). A repair pathway that functions predominantly in the G0/G1 and G2 phases of the cell cycle and repairs double-strand DNA breaks by blunt end ligation independently of sequence homology.

CRISPR technology

A technique that is now commonly used worldwide for gene editing and, notably, for generating knockout systems.

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Ceccaldi, R., Sarangi, P. & D'Andrea, A. The Fanconi anaemia pathway: new players and new functions. Nat Rev Mol Cell Biol 17, 337–349 (2016). https://doi.org/10.1038/nrm.2016.48

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