Molecular Genetics of Fanconi Anaemia


Cells derived from Fanconi anaemia (FA) patients display hypersensitivity to deoxyribonucleic acid (DNA) cross‐linking agents such as MMC and DEB. Treatment with these agents induces an abnormally prolonged cell cycle arrest in S phase and an accumulation of cells with 4N DNA. Based on this response, the FA pathway has been hypothesised to function in sensing DNA damage induced by these agents and in initiating its repair. This hypothesis has been supported by work elucidating the interactions of FA proteins with proteins known to be involved in DNA‐damage sensing, signalling and repair. Additionally, a significant body of work has pointed to a role of the FA pathway in the cellular response to oxidative stress. Although the exact mechanisms and functions of the FA pathway are yet to be discovered, the interaction of the members of the FA pathway with proteins associated with DNA repair, cellular signalling and oxidative stress management leads to the hypothesis that the FA pathway proteins serve many varied functions throughout the cell.

Key Concepts:

  • The FA pathway overlaps significantly with other DNA repair pathways such as homologous recombination, translesion synthesis and mismatch repair.

  • FA pathway proteins are involved in the intricate cellular signalling that occurs following DNA damage.

  • FA pathway proteins are involved in regulating oxidative stress.

  • FA mutant cells display hypersensitivity to DNA damage, particularly DNA crosslink's.

  • FA patients are particularly prone to malignancy, especially myeloid leukemia and squamous cell carcinomas of the head and neck and genitourinary track.

Keywords: Fanconi anaemia; DNA damage; DNA repair; cancer susceptibility; DNA damage hypersensitivity

Figure 1.

The FA pathway proteins: The FA pathway is composed of at least 13 genes. Each of these genes, when biallelically mutated, causes FA. The encoded proteins can be subdivided within the FA pathway into three groups: proteins that make up the core complex, the FANCD2 and FANCI proteins which compose the ID complex and five downstream effector proteins: FANCD1/BRCA2, FANCJ/BRIP1/BACH1, FANCN/PALB2, FANCO/RAD51C and FANCP/SLX4. Following treatment with DNA crosslinking agents or during S phase of the cell cycle, FANCD2 and FANCI become monoubiquitylated. An intact core complex is required for these modifications, which result in the relocation of the two proteins to chromatin within cells. Within chromatin, FANCD2 and FANCI colocalise with DNA repair proteins including the downstream effector, FA proteins, at sites of DNA damage in nuclear foci. FA proteins are in blue.

Figure 2.

Homologous recombination: In response to the forms of DNA damage such as DSBs, the mammalian histone, H2A variant H2AX, is incorporated into DNA at sites surrounding the damage and is phosphorylated at serine 139 to generate γH2AX (a). The γH2AX histone variant serves as a marker of DSBs and helps to initiate the accumulation of DNA‐damage sensing and repairing proteins such as NBS1 and BRCA1 to these sites of damage (b). These damage sensing proteins recruit nucleases which resects the DNA surrounding the damage in order to produce 3′ overhangs, which are necessary for the next step of strand invasion. BRCA2 nucleates RAD51 onto the 3′ DNA overhangs in order to stabilise the ssDNA and to promote its invasion of its complementary duplex (c). Strand invasion results in D‐loop structure formation and subsequent DNA synthesis using the complementary strand as a template (d). The D‐loop structure is resolved by either synthesis dependent strand annealing (SDSA) or double strand break repair (DSBR). In the SDSA pathway, the D loop is unwound and the ssDNA strand anneals with its complementary ssDNA on the other side of the DSB. Gap‐filling DNA synthesis and ligation ensue, resulting in noncrossover products (e). In the DSBR pathway, the second end of the DSB is captured to form an intermediate structure containing two Holliday junctions (HJ) which are extended by gap filling DNA synthesis and ligation. Resolution of the HJ can result in either crossover or noncrossover products. The BLM helicase promotes noncrossover product formation and resolution of Holliday junction structures (f, g). FA proteins interact with several of the proteins involved in HR including H2AX, BRCA1, RAD51 and BLM.

Figure 3.

Translesion synthesis: To continue replicating through sites of DNA damage which block replicative polymerases and lead to replication fork stalling, (a) cells employ the use of TLS polymerases. Upon encountering DNA damage, RAD6 and RAD18 ubiquitylate PCNA, decreasing its affinity for replicative polymerases and increasing its affinity for TLS polymerases that contain an ubiquitin‐binding motif (b). This increase in affinity results in polymerase switching and replicating through sites of DNA damage using the appropriate TLS polymerase. After the replication machinery has passed the site of damage, the TLS polymerase falls off DNA, PCNA gets deubiquitylated by USP1 and replicative polymerases are able to once again interact with PCNA and resume normal replication (c). FA proteins interact with several of the proteins involved in TLS, including PCNA, the TLS polymerase REV1 and USP1.



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Further Reading

Deans AJ and West SC (2011) DNA interstrand crosslink repair and cancer. Nature Reviews Cancer 11(7): 467–480.

Sengerova B, Wang AT and McHugh PJ (2011) Orchestrating the nucleases involved in DNA interstrand cross‐link (ICL) repair. Cell Cycle 10(23): 3999–4008.

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How to Cite close
Green, Allison M, and Kupfer, Gary M(Dec 2012) Molecular Genetics of Fanconi Anaemia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024322]