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Anaemia and Haemaglobinopathies
The Biology of Fanconi Anaemia
a report by
Gary M Kupfer and Gang Zhi
Department of Pediatrics, Yale University School of Medicine, New Haven
Fanconi anaemia (FA) is a genetic, life-threatening disorder
featuring Protein Biochemistry of Fanconi Anaemia
progressive bone marrow failure, birth defects, leukaemia, increased
incidence of solid tumours, spontaneous chromosomal instability and Core Complex Formation
hypersensitivity to cross-linking reagents.
Because of FA’s relationship Eight FA genes (FANCA, FANCC, FANCB, FANCG, FANCF, FANCE, FANCL
to DNA damage hypersensitivity and its association with susceptibility to and FANCM) encode for members of a multi-subunit protein complex
neoplastic transformation, the FA research field has gained much termed the FA core complex. Although the stoichiometry is unclear, most
attention in recent decades, especially after the discovery of the subunits are required for general complex stability and proper nuclear
connection between FA and the well-known breast cancer (BRCA) genes. localisation, which is essential for mono-ubiquitilation of the downstream
FANCA and FANCG readily associate and stabilise
Clinical Features each other.
Other known interacting pairs within the FA core complex
FA is a very heterogeneous condition clinically, and about 70% of include FANCE/FANCC
FANCF functions as a
patients display a wide variety of abnormalities, classic among which molecular adaptor, bridging between the subcomplexes A:G and C:E,
are missing or misshapen thumbs and radii, kidney, gastrointestine and whereas FANCM may link the subcomplex B:L to the subcomplex A:G.
neurocognitive and developmental delay.
The most important The FA core complex is also reported to weakly associate with other DNA
clinical feature of FA is marrow failure in the form of aplastic anaemia, repair proteins, including Bloom’s helicase,
myelodysplastic syndrome or acute myeloid leukaemia (AML).
The replication protein A.
Although the functional significance of these
number of FA children surviving childhood has greatly increased with inter-complex associations is uncertain, they nevertheless imply a role of
the advent of improved outcomes after bone marrow transplantation FA in DNA damage response. The amount of the chromatin-bound
for bone marrow failure and AML, but those patients surviving until fraction of FA complex increases in the S phase when the FA pathway is
adulthood have to face a greatly increased risk of solid tumours, activated,
and is facilitated by FANCM.
Similar results were observed
typically squamous cell carcinomas such as head and neck and in a newly developed cell-free Xenopus system.
The loading and
unloading of the xFA core complex is strictly dependent on entry and exit
during the S phase, supporting the role of FA in DNA replication.
Because FANCD1/BRCA2 conveys an inherited risk of breast, ovarian and
pancreatic cancer for individuals carrying a single mutated allele, the FA Mono-ubiquitilation of FANCD2
pathway is thought to be involved in cancer development. Many studies FANCD2 is mono-ubiquitilated on lysine 561 in response to DNA
support the notion that somatic inactivation of the FA pathway may damage
as well as S-phase progression,
which is dependent on the FA
contribute to the pathogenesis of sporadic cancers, including AML.
For core complex. This is a pivotal event to activate the FA pathway. FA-D2
pancreatic cancer, although screens for germline mutations in FANCC, cell lines expressing mutant FANCD2 (K561R) are as sensitive to MMC as
FANCA and FANCG failed to detect any pathogenic alleles in familial parental cell lines. The whole FA core complex is hypothesised to be the
truncations of FANCC were found in sporadic pancreatic ubiquitin E3 ligase for FANCD2 with FANCL as the catalytic subunit.
cancers of early-onset cases.
Expression of FANCF is decreased in most FANCE may serve as a link between FANCD2 and the core complex, as it
ovarian cancers compared with those in normal ovarian tissue,
in part is found to be bound to both.
In addition, knockdown of the E2 ligase
because of methylation of the FANCF promoter, suggesting a role for UBE-2T, a binding partner of FANCL, leads to a drastic reduction of the
epigenetic modifications in FA tumorigenesis.
Restoration of this level of mono-ubiquitilated FANC-D2 (FANCD2-L isoform).
pathway is associated with demethylation of FANCF, leading to acquired
Gary M Kupfer is Chief of the Section of Pediatric Hematology-Oncology in the Department of
Pediatrics at Yale University School of Medicine, New Haven, Connecticut. Dr Kupfer received
Fanconi Anaemia Genes
his BSc from the University of Florida and his MD from Johns Hopkins University, and trained in
paediatrics and haematology-oncology at the University of Pennsylvania and Harvard Medical
At the cellular level, the distinguishing and diagnostic features of FA are
spontaneous genomic instability and hypersensitivity to DNA interstrand
cross-linkers such as mitomycin C (MMC) and diepoxybutane (DEB). FA
complementation groups were established by the pair-wise fusion of
Gang Zhi is a graduate student in the Cellular and Molecular Biology programme at the
patient-derived cell lines and the subsequent resistance to genotoxic
University of Virginia School of Medicine, and is completing his dissertation at Dr Kupfer’s
laboratory at Yale University. Mr Zhi has a primary interest in cancer biology and is interested
reagents. The genes were subsequently cloned via expression,
in the signal transduction pathway of the DNA damage response. Mr Zhi obtained his BSc at
purification, positional and candidate approaches.
A summary of
the Fudan University, Shanghai, China.
identified FA genes is shown in Table 1.
© TOUCH BRIEFINGS 2007 59
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