FANCA

Source: Wikipedia, the free encyclopedia.
FANCA
Identifiers
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000187741

ENSMUSG00000032815

UniProt

O15360

Q9JL70

RefSeq (mRNA)

NM_000135
NM_001018112
NM_001286167
NM_001351830

NM_016925

RefSeq (protein)

NP_000126
NP_001018122
NP_001273096
NP_001338759

NP_058621

Location (UCSC)Chr 16: 89.73 – 89.82 MbChr 8: 124 – 124.05 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a

blood cells.[6]

Mutations involving the FANCA gene are associated with many somatic and congenital defects, primarily involving phenotypic variations of

acute myeloid leukaemia.[7]

Function

The Fanconi anaemia complementation group (FANC) currently includes FANCA,

FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, and FANCL. The previously defined group FANCH is the same as FANCA. The members of the Fanconi anaemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. The FANCA gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms.[5]

Fanconi anaemia group A protein
Identifiers
SymbolFanconi_A
PfamPF03511
InterProIPR003516
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Gene and protein

In humans, the gene FANCA is 79 kilobases (kb) in length, and is located on

DNA damage, catalysing activation of the FA/BRCA DNA damage-response pathway,[10] leading to repair.[11]

FANCA binds to both single-stranded (ssDNA) and double-stranded (dsDNA) DNAs; however, when tested in an electrophoretic mobility shift

dsDNA. FANCA also binds to RNA with a higher affinity than its DNA counterpart.[12] FANCA requires a certain number of nucleotides for optimal binding, with the minimum for FANCA recognition being approximately 30 for both DNA and RNA. Yuan et al. (2012) found through affinity testing FANCA with a variety of DNA structures that a 5'-flap or 5'-tail on DNA facilitates its interaction with FANCA, while the complementing C-terminal fragment of Q772X, C772-1455, retains the differentiated nucleic acid-binding activity (i.e. preferencing RNA before ssDNA and dsDNA), indicating that the nucleic acid-binding domain of FANCA is located primarily at the C terminus, a location where many disease-causing mutations are found.[12]

FANCA is ubiquitously expressed at low levels in all cells

leukaemia cells, FA proteins are readily detectable by immunoprecipitation.[15]

Clinical significance

mitomycin-C (MMC) when compared to normal cells. The primary diagnostic test for Fanconi anaemia is based on the increased chromosomal breakage seen in afflicted cells after exposure to these agents – the DEB/MMC stress test. Other features of the Fanconi anaemia cell phenotype also include abnormal cell cycle kinetics (prolonged G2 phase), hypersensitivity to oxygen, increased apoptosis and accelerated telomere shortening.[6][16]

FANCA mutations are by far the most common cause of Fanconi anaemia, accounting for between 60-70% of all cases. FANCA was cloned in 1996

Alu
mediated recombination. A highly relevant observation is that different mutations produce Fanconi anaemia phenotypes of varying severity.

Patients

compound heterozygotes, diagnostic screening for mutations is difficult. Certain founder mutations can also occur in some populations, such as the deletion exon 12-31 mutation, which accounts for 60% of mutations in Afrikaners.[22]

Involvement in FA/BRCA pathway

In cells from Fanconi anaemia patients, FA core complex induction of

coimmunoprecipitation from in vitro synthesis, and coimmunoprecipitation from cell extracts shows that the site of interaction is between the terminal amino group of FANCA and the central part of BRCA1, located within amino acids 740–1083.[16][26]

However, as FANCA and

ubiquitination
of FANCD2, a later functioning protein in the FA path, promoting ICL and DNA repair.

FANCA’s emerging putative and clearly integral function within activation the FA core complex also provides an explanation for its particularly high correlation with mutations causing Fanconi anaemia. Whilst many FANC protein mutations account for only 1% of the total observed cases,

upregulation also increases expression of FANCG in cells, and the fact this transduction is not mutual – FANCG upregulation does not cause increased expression of FANCA – suggests that FANCA is not only the primary stabilizing protein in the core complex, but may act as a natural regulator in patients who would otherwise suffer from mutations in FANC genes other than FANCA or FANCD2.[28][29]

Participation in haematopoiesis

FANCA is hypothesised to play a crucial role in adult (definitive)

megaloblastic anaemia around the age of 7, with this macrocytosis being the first haematological marker.[7] Defective in vitro haematopoiesis has been recorded for over two decades resulting from mutated FANCA proteins, in particular developmental defects such as impaired granulomonocytopoiesis due to FANCA mutation.[30]

Studies using clonogenic

myeloid progenitors (CFU-GM) have also shown that the frequency of CFU-GM in normal bone marrow increased and their proliferative capacity decreased exponentially with age, with a particularly marked proliferative impairment in Fanconi anaemia afflicted children compared to age-matched healthy controls.[31][32]
As haematopoietic progenitor cell function begins at birth and continues throughout life, it is easily inferred that prolonged incapacitation of FANCA protein production results in total haematopoietic failure in patients.

Potential impact on erythroid development

The three distinct stages of

erythrocytes are the most common blood cell type and characteristically most similar across mammalian species.[33] Primitive and foetal erythrocytes however, have markedly different characteristics. These include: they are larger in size (primitive even more so than foetal), circulate during early stages of development with a shorter lifespan, and, in particular, primitive cells are nucleated.[34]

As the reasons for these disparities are not well understood, FANCA may be a gene responsible for instigating these morphological differences when considering its variations in erythrocyte expression.

megaloblastic anaemia around age 7,[6]
a haematological disorder marked physically by proliferation-impaired, oversized erythrocytes, it is possible that the size and proliferative discrepancies between primitive, foetal and adult erythroid lineages may be explained by FANCA expression. As FANCA is also linked to cell-cycling and its progression from G2 phase, the stage impaired in megaloblastic anaemia, its expression in definitive proerythroblast development may be an upstream determinant of erythroid size.

Implications in cancer

FANCA mutations have also been implicated in increased risks of

acute myeloid leukaemia.[6]

Mouse knockout

stem cell transplant or gene therapies.[6][37]

Both female and male mice homozygous for a FANCA mutation show hypogonadism and impaired fertility.[38] Homozygous mutant females exhibit premature reproductive senescence and an increased frequency of ovarian cysts.

In spermatocytes, the FANCA protein is ordinarily present at a high level during the pachytene stage of meiosis.[39] This is the stage when chromosomes are fully synapsed, and Holliday junctions are formed and then resolved into recombinants. FANCA mutant males exhibit an increased frequency of mispaired meiotic chromosomes, implying a role for FANCA in meiotic recombination. Also apoptosis is increased in the mutant germ cells. The Fanconi anemia DNA repair pathway appears to play a key role in meiotic recombination and the maintenance of reproductive germ cells.[39]

Loss of FANCA provokes neural progenitor apoptosis during forebrain development, likely related to defective DNA repair.[40] This effect persists in adulthood leading to depletion of the neural stem cell pool with aging. The Fanconi anemia phenotype can be interpreted as a premature aging of stem cells, DNA damages being the driving force of aging.[40] (Also see DNA damage theory of aging.)

Interactions

FANCA has been shown to

interact
with:

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000187741 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032815 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c "Entrez Gene: FANCA Fanconi anemia, complementation group A".
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