jeudi 2 août 2012

Mutated genes in cancer (83) – FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, PALB2 (FANCN), RAD51C (FANCO), BRCA1





FANCA

In databases:

Ensembl (http://www.ensembl.org/index.html): ENSG00000187741
UniProt (http://www.uniprot.org/): O15360
GeneCards (http://www.genecards.org/): FANCA
HGNC (http://www.genenames.org/): 3582 or FANCA

Gene locus:

16q24.3

Protein name:

Fanconi anemia, complementation group A

Protein Size:

1455 amino acids; about 163 kDa



FANCB

In databases:

Ensembl (http://www.ensembl.org/index.html): ENSG00000181544
UniProt (http://www.uniprot.org/): Q8NB91
GeneCards (http://www.genecards.org/): FANCB
HGNC (http://www.genenames.org/): 3583 or FANCB

Gene locus:

Xp22.2

Protein name:

Fanconi anemia, complementation group B

Protein Size:

859 amino acids; about 98 kDa



FANCC

In databases:

Ensembl (http://www.ensembl.org/index.html): ENSG00000158169
UniProt (http://www.uniprot.org/): Q00597
GeneCards (http://www.genecards.org/): FANCC
HGNC (http://www.genenames.org/): 3584 or FANCC

Gene locus:

9q22.3

Protein name:

Fanconi anemia, complementation group C

Protein Size:

558 amino acids; about 63 kDa



BRCA2 (FANCD1)

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000139618
UniProt (http://www.uniprot.org/): P51587
GeneCards (http://www.genecards.org/): BRCA2
HGNC (http://www.genenames.org/): 1101 or BRCA2

Gene locus:

13q12-q13

Protein name:

Breast cancer 2, early onset

Protein Size:
3418 amino acids; about 384 kDa



FANCD2

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000144554
UniProt (http://www.uniprot.org/): Q9BXW9
GeneCards (http://www.genecards.org/): FANCD2
HGNC (http://www.genenames.org/): 3585 or FANCD2

Gene locus:

3p25.3

Protein name:

Fanconi anemia, complementation group D2

Protein Size:

1471 amino acids; about 166 kDa



FANCE

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000112039
UniProt (http://www.uniprot.org/): Q9HB96
GeneCards (http://www.genecards.org/): FANCE
HGNC (http://www.genenames.org/): 3586 or FANCE

Gene locus :

6p21-22

Protein name:

Fanconi anemia, complementation group E

Protein Size:

536 amino acids; about 59 kDa



FANCF

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000183161
UniProt (http://www.uniprot.org/): Q9NPI8
GeneCards (http://www.genecards.org/): FANCF
HGNC (http://www.genenames.org/): 3587 or FANCF

Gene locus

11p15

Protein name:

Fanconi anemia, complementation group F

Protein Size:

374 amino acids; about 42 kDa



FANCG

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000165281
UniProt (http://www.uniprot.org/): O15287
GeneCards (http://www.genecards.org/): FANCG
HGNC (http://www.genenames.org/): 3588 or FANCG

Gene locus:

9p13

Protein name:

Fanconi anemia, complementation group G

Protein Size:

622 amino acids; about 69 kDa



FANCI

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000140525
UniProt (http://www.uniprot.org/): Q9NVI1
GeneCards (http://www.genecards.org/): FANCI
HGNC (http://www.genenames.org/): 25568 or FANCI

Gene locus :

15q26.1

Protein name:

Fanconi anemia, complementation group I

Protein Size:

1328 amino acids; about 149 kDa



BRIP1 (alias FANCJ)

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000136492
UniProt (http://www.uniprot.org/): Q9BX63
GeneCards (http://www.genecards.org/): FANCJ
HGNC (http://www.genenames.org/): 20473 or BRIP1

Gene locus:

17q23.2

Protein name:

BRCA1 interacting protein C-terminal helicase 1 (BRIP1) or Fanconi anemia, complementation group J (FANCJ)

Protein Size:

1249 amino acids; about 141 Da



FANCL

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000115392
UniProt (http://www.uniprot.org/): Q9NW38
GeneCards (http://www.genecards.org/): FANCL
HGNC (http://www.genenames.org/): 20748 or FANCL
EC number : EC 6.3.2.

Gene locus:

2p16.1

Protein name:

Fanconi anemia, complementation group L

Protein Size:

375 amino acids; about 43 kDa



FANCM

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000187790
UniProt (http://www.uniprot.org/): Q8IYD8
GeneCards (http://www.genecards.org/): FANCM
HGNC (http://www.genenames.org/): 23168 or FANCM
EC number : EC 3.6.1

Gene locus:

14q21.2

Protein name:

Fanconi anemia, complementation group M

Protein Size:

2048 amino acids; about 232 kDa



PALB2 (alias FANCN)

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000083093
UniProt (http://www.uniprot.org/): Q86YC2
GeneCards (http://www.genecards.org/): PALB2
HGNC (http://www.genenames.org/): 26144 or PALB2

Gene locus :

16p12.2

Protein name:

Partner and localizer of BRCA2

Protein Size:

1186 amino acids; about 131 kDa



RAD51C (alias FANCO)

In databases :

Ensembl (http://www.ensembl.org/index.html): ENSG00000108384
UniProt (http://www.uniprot.org/): O43502
GeneCards (http://www.genecards.org/): RAD51C
HGNC (http://www.genenames.org/): 9820 or RAD51C

Gene locus:

17q25.1

Protein name:

RAD51 homolog C (S. cerevisiae)

Protein Size:

376 amino acids; about 42 kDa




Function:

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.

Cancer-related alterations:

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) agents.

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 cancer.


References (open access):

Expanded roles of the Fanconi anemia pathway in preserving genomic stability. Kee Y, D'Andrea AD. Genes Dev. 2010 Aug 15;24(16):1680-94.

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.

RAD51C: a novel cancer susceptibility gene is linked to Fanconi anemia and breast cancer. Somyajit K, Subramanya S, Nagaraju G. Carcinogenesis. 2010 Dec;31(12):2031-8.

Susceptibility pathways in Fanconi's anemia and breast cancer. D'Andrea AD. N Engl J Med. 2010 May 20;362(20):1909-19.

Mutagenic repair of DNA interstrand crosslinks. Shen X, Li L. Environ Mol Mutagen. 2010 Jul;51(6):493-9.


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