European Haematology Review 2007

Kupfer.qxp 15/2/08 11:33 am Page 61
The Biology of Fanconi Anaemia
Figure 1: Model of the Fanconi Anaemia Pathway
DNA damage/replication DNA recombination
fork stalling and repair
Nuclear FA
core complex
FANCI
A
Ub
FAAP
100
C
G
E
D2-L
M
RAD51
J
E F XRCC3
B
G
BRCA2
L
N
FA effector
complex?
I
FANCD2-S FANCD2-L
Ub
FANCI FANCI Ub
Increased apoptosis may be mediated via TNF-related apoptosis-inducing redox activities such as NADPH cytochrome P450 reductase
72
and
ligand in FA-A cells, although FA-C cells are resistant to TRAIL.
66,67
Protein glutathione S-transferase.
73
FANCG protein interacts with cytochrome
kinase regulated by RNA (PKR) plays a critical role in cell growth and P450 2E1, a P450 protein known to be involved in redox biotransformation
apoptosis
68
and is implicated in the FA pathway. In primary human bone of xenobiotics, including MMC.
74
Microarray experiments show consistent
marrow cells, mutation in FANCA, FANCC or FANCG markedly increases overexpression of proteins involved in oxidative metabolism, including
the association between PKR and FANCC, leading to hyperactivation of nuclear factor 1, heat shock protein 70kDa and cyclo-oxyenase 2 in FA
PKR and hypersensitivity to cytokine-mediated cytotoxicity.
69,70
FANCC mutant cells.
75,76
The role of the FA pathway in oxidative stress response is
binds to the signal transducer and activator of transcription 1 (STAT1) further supported by data from primary and immortalised cell cultures,
following IFN-γ treatment and is required for proper docking of STAT1 at indicating a pro-oxidant state in FA cells.
77,78
More significantly,
the IFN-γ receptor α-chain
71
for survival cues. Together, augmented activity chromosome abnormalities,
79–81
cell-cycle defects
82
and pro-apoptotic
of PKR and failed activation of STAT1 by IFN-γ may thus tip the balance propensity
83,84
in FA cells can be corrected by antioxidant enzymes or low-
from survival to death in FA-C haematopoietic progenitor cells. molecular-weight antioxidants (such as thioredoxin) or hypoxia.
85
A recent
study found that hypoxia–re-oxygenation cycles mimicking the condition
Fanconi Anaemia Oxygen Sensitivity faced by migrating haematopoietic cells induce premature senescence
There is an extensive body of evidence indicating that the FA pathway has arrest and inhibit expansion of fancc-/- BM cells, suggesting a novel
a role in oxidative stress response. FANCC associates with proteins with mechanism for bone marrow failure in FA.
86
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