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The emerging genetic and molecular basis of Fanconi anaemia

Key Points

  • Fanconi anaemia (FA) is a rare, autosomal, recessive disease that causes life-threatening bone marrow failure, diverse somatic abnormalities and cancer susceptibility. It is characterized by chromosomal instability and hypersensitivity to crosslinking agents, and is genetically heterogeneous.

  • The DNA-damage-response pathway that is altered in FA remains to be elucidated, but the cloning and recent characterization of several FA genes have provided clues as to their function.

  • FA patients are assigned to one of eight FA complementation groups. For six of these, disease genes have been found: FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG.

  • The predicted proteins of these genes lack homologues in non-vertebrates, except for FANCD2. All of them, except for FANCD2, are essential for the assembly of a multiprotein nuclear complex, which is required for FANCD2 to be monoubiquitylated to its active form.

  • Monoubiquitylated FANCD2 co-localizes with BRCA1 to subnuclear foci, the number of which increases upon DNA damage. There is also evidence that the FA pathway has a cytoplasmic component(s).

  • A proportion of FA patients show phenotypic reversion to wild type in lymphocytes. This is due to a correction of the gene defect in haematopoietic stem cells by mitotic recombination, fuelling hopes that gene therapy could be used to treat the life-threatening bone marrow failure that develops in FA patients.

Abstract

The past few years have witnessed a considerable expansion in our understanding of the pathways that maintain chromosome stability in dividing cells through the identification of genes that are mutated in certain human chromosome instability disorders. Cells that are derived from patients with Fanconi anaemia (FA) show spontaneous chromosomal instability and mutagen hypersensitivity, but FA poses a unique challenge as the nature of the DNA-damage-response pathway thought to be affected by the disease has long been a mystery. However, the recent cloning of most of the FA-associated genes, and the characterization of their protein products, has provided tantalizing clues as to the molecular basis of this disease.

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Figure 1: Complementation groups in Fanconi anaemia.
Figure 2: Relative prevalences of Fanconi anaemia complementation groups.
Figure 3: Complementation cloning.
Figure 4: Mutations in FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG.
Figure 5: A model of the Fanconi anaemia pathway.
Figure 6: Co-localization of FANCD2 and BRCA1.

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Acknowledgements

We thank our lab members for stimulating discussions and valuable comments on the manuscript. Work in our laboratories is supported by grants from the Dutch Cancer Society, the Netherlands Organization for Scientific Research, the FA Research Fund, Inc., Eugene, Oregon, the European FA patient support organizations, and the Medical Research Council. We apologize to colleagues whose work could not be cited because of space limitations.

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Related links

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DATABASE LINKS

FANCD

BRCA1

hereditary non-polyposis colorectal cancer

Bloom syndrome

Werner syndrome

FA-A

FA-G

FANCC

FANCA

FANCG

FANCF

FANCE

FA-D2

Fancc

Fanca

FA-C

NBS1

MRE11

FA-D1

HGPRT

DNA-PK

XRCC4

RAD50

RAD51

FAZF

Brca1

NADPH cytochrome P450 reductase

Sod1

serum α-fetoprotein

ataxia-telangiectasia

FURTHER INFORMATION

Manuel Buchwald's lab

Fanconi Anaemia Mutation Database

FA Research Fund, Inc.

Glossary

APLASTIC ANAEMIA

Bone marrow failure. This results in a peripheral deficiency of all bone-marrow-derived haematopoietic lineages, such as red blood cells, platelets and leukocytes. There are many causes of this potentially fatal clinical syndrome.

ACUTE MYELOID LEUKAEMIA

(AML) Also known as acute non-lymphocytic leukaemia (ANLL), this is a heterogeneous group of leukaemias in which the lymphoblast cells that give rise to granulocytes do not mature and become too numerous. These immature blast cells are then found in the blood and the bone marrow.

SQUAMOUS CELL CARCINOMAS

Cancers that arise from squamous epithelial cells or 'keratinocytes', which cover the skin and oral cavity.

CROSSLINKING AGENTS

These agents form a specific type of lesion in double-stranded DNA — chemical crosslinks between the two DNA strands (interstrand crosslinks) and between adjacent bases on the same strand (intrastrand crosslinks). These modifications obstruct DNA replication and, because they can modify both strands, specific repair pathways are required to maintain genomic integrity in cells exposed to them.

CARETAKER GENES

Genes that encode the proteins that function to protect the genome against alterations.

NUCLEOTIDE EXCISION REPAIR

A DNA-repair pathway that removes DNA damage (such as ultraviolet-light-induced thymidine dimers) and bulky DNA adducts by excising the region of DNA that contains the damaged base(s). The single-stranded gap is filled in by using the intact strand as a template.

MICROCELL

An experimentally produced cell-like structure, which contains a micronucleus in which one or a few chromosomes are present. They can be used as a vector to transfer genetic material to a normal cell by cell fusion.

SERIAL TRANSPLANTATION

When a donor tissue is used for another transplant after engraftment in a recipient.

MITOTIC RECOMBINATION

A crossover between two homologous double-stranded DNA molecules that leads to a physical exchange of DNA and genetic information. This recombination occurs frequently during meiosis, but is relatively rare during mitosis. As a consequence of mitotic recombination, cells can undergo a 'loss of heterozygosity' or gene conversion.

GENE CONVERSION

A specific type of recombination, which results in non-reciprocal genetic exchange, in which the sequence of one DNA strand is used to alter the sequence of the other.

RAD51

The human homologue of bacterial RecA. RAD51 is required for homologous recombination, during which it promotes strand invasion. RAD51 forms nucleoprotein filaments around single-stranded DNA.

RAD50

RAD50 forms a complex with MRE11 and NBS1 and is essential for double-stranded DNA-break repair by homologous recombination and non-homologous end-joining.

RING-FINGER MOTIF

A structure seen in many DNA-binding proteins; it is composed of a polypeptide loop held in a hairpin bend bound to a zinc atom.

UBIQUITIN LIGASE

An enzyme that couples the small (7 kDa) protein ubiquitin to lysine residues on a target protein, thus targeting it for degradation by the proteasome. It is less clear how monoubiquitylation targets proteins to cellular compartments and modifies their activity.

V(D)J RECOMBINATION

A specialized form of recombination that assembles the genes that encode lymphocyte antigen receptors from variable (V), diversity (D) and joining (J) gene segments. DNA double-stranded breaks are introduced between the V, D and J segments and DNA repair/recombination proteins then join the segments together.

ERROR-PRONE REPAIR PATHWAYS

DNA lesions can be repaired by many competing pathways. Some of these pathways repair damaged DNA with reduced fidelity, giving rise to new mutations.

TRANSCRIPTION-COUPLED REPAIR

A specialized pathway that facilitates the repair of damaged DNA during transcription, in which the transcribed strand of active genes is preferentially repaired. This process is defective in the genetic disease, Cockayne syndrome.

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Joenje, H., Patel, K. The emerging genetic and molecular basis of Fanconi anaemia. Nat Rev Genet 2, 446–458 (2001). https://doi.org/10.1038/35076590

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