The proteins encoded by the genes
presented here are believed to function in a common DNA
repair signaling pathway, the Fanconi
Anemia (FA) pathway, which closely cooperates with other DNA repair proteins
for resolving DNA interstrand cross-links (ICLs) during DNA replication. ICLs
are among the most deleterious DNA lesions, since they block DNA replication
and transcription. DNA ICLs can be caused by endogenous sources such as nitrous
acid and aldehydes, or exogenous agents such as cisplatin and its derivatives.
A central event in the resolution of DNA
ICLs is the monoubiquitination of FANCD2 and
FANCI upon DNA damage, which is mediated
by a group of upstream FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG,
FANCL, and FANCM) that are assembled into a large nuclear E3 ubiquitin ligase complex,
termed the ‘‘FA core complex’’ (Kennedy and D’Andrea 2005; Wang 2007).
The monoubiquitinated FANCD2/FANCI
heterodimer was shown to play multiple roles in the pathway (Knipscheer et al.
2009), and to functionally interact with downstream FA proteins such as FANCD1
(or BRCA2), FANCN (or PALB2), and FANCJ (or BRIP1), and their associated
proteins, BRCA1 or RAD51C.
FA is a genetically heterogeneous,
autosomal recessive disorder characterized by bone marrow failure,
developmental abnormalities, and increased incidence of cancers. At the
cellular level, FA cells display increased chromosomal aberrations,
particularly radials, and hypersensitivity to DNA interstrand cross-link (ICL)
FA is caused by mutations in at least 13
distinct genes (FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG,
FANCI, FANCJ, FANCL, FANCM, and FANCN). About 66% of FA cases are caused by
mutations in FANCA, 10% by mutations in FANCC and 10% by mutations in FANCG.
In FA genes, various germinal alterations
(nucleotide substitutions, deletions, or insertions) have been described.
Somatic point mutations are rare.
Principal cancers observed in biallelic mutation
carriers (phenotype of FA patients) are acute myeloid leukemia (AML), head and
neck squamous cell carcinoma (SCC), anogenital tumors. In the case of biallelic
mutation in FANCD1/BRCA2 or FANCN/PALB2, aggressive FA may be observed,
associated to childhood solid tumors (Wilms tumor and medulloblastoma).
In carriers of monoallelic mutation, only those with
alteration in FANCD1/BRCA2 are highly susceptible to (breast) cancer, while
carriers of FANCJ/BRIP1 or FANCN/PALB2 have a low-risk of developing breast
References (open access):
Expanded roles of the Fanconi anemia pathway in
preserving genomic stability. Kee Y, D'Andrea AD. Genes Dev. 2010 Aug
Mutational analysis of FANCL, FANCM and the recently
identified FANCI suggests that among the 13 known Fanconi Anemia genes, only
FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition. García
MJ, Fernández V, Osorio A, Barroso A, Fernández F, Urioste M, Benítez J.
Carcinogenesis. 2009 Nov;30(11):1898-902.