Summary: Fanconi anaemia group A protein
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FANCA Edit Wikipedia article
|Fanconi anemia, complementation group A|
|Symbols||; FA; FA-H; FA1; FAA; FACA; FAH; FANCH|
|RNA expression pattern|
Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a protein which in humans is encoded by the FANCA gene. It belongs to the Fanconi anaemia complementation group (FANC) family of genes of which 12 complementation groups are currently recognized and is hypothesised to operate as a post-replication repair or a cell cycle checkpoint. FANCA proteins are involved in inter-strand DNA cross-link repair and in the maintenance of normal chromosome stability that regulates the differentiation of haematopoietic stem cells into mature blood cells.
Mutations involving the FANCA gene are associated with many somatic and congenital defects, primarily involving phenotypic variations of Fanconi anaemia, aplastic anaemia, and forms of cancer such as squamous cell carcinoma and acute myeloid leukaemia.
The Fanconi anaemia complementation group (FANC) currently includes FANCA, FANCB, 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.
Gene and protein
In humans, the gene FANCA is 79 kilobases (kb) in length, and is located on chromosome 16 (16q24.3). The FANCA protein is composed of 1455 amino acids. Within cells, the major purpose of FANCA belongs to its putative involvement in a multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL/PHF9 and FANCM. In complex with FANCF, FANCG and FANCL, FANCA interacts with HES1. This interaction has been proposed as essential for the stability and nuclear localization of FA core complex proteins. The complex with FANCC and FANCG may also include EIF2AK2 and HSP70. In cells, FANCA involvement in this ‘FA core complex’ is required for the activation of the FANCD2 protein to a monoubiquitinated isoform (FANCD2-Ub) in response to DNA damage, catalysing activation of the FA/BRCA DNA damage-response pathway, leading to repair.
FANCA binds to both single-stranded (ssDNA) and double-stranded (dsDNA) DNAs; however, when tested in an electrophoretic mobility shift assay, its affinity for ssDNA is significantly higher than for dsDNA. FANCA also binds to RNA with a higher affinity than its DNA counterpart. 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.
FANCA is ubiquitously expressed at low levels in all cells with subcellular localisation in primarily nucleus but also cytoplasm corresponding with its putative caretaker role in DNA damage-response pathways, and FA complex formation. The distribution of proteins in different tissues is not well understood currently. Immunochemical study of mouse tissue indicates that FANCA is present at a higher level in lymphoid tissues, the testis and the ovary, and though the significance of this is unclear, it suggests that the presence of FA proteins might be related to cellular proliferation. For example, in human immortalized lymphoblasts and leukaemia cells, FA proteins are readily detectable by immunoprecipitation.
Mutations in this gene are the most common cause of Fanconi's anaemia. Fanconi anaemia is an inherited autosomal recessive disorder, the main features of which are aplastic anaemia in childhood, multiple congenital abnormalities, susceptibility to leukemia and other cancers, and cellular hypersensitivity to interstrand DNA cross-linking agents. Generally cells from Fanconi anaemia patients show a markedly higher frequency of spontaneous chromosomal breakage and hypersensitivity to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) and 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.
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 and it is one of the largest FA genes. Hundreds of different mutations have been recorded with 30% point mutations, 30% 1-5 base pair microdeletions or microinsertions, and 40% large deletions, removing up to 31 exons from the gene. These large deletions have a high correlation with specific breakpoints and arise as a result of Alu mediated recombination. A highly relevant observation is that different mutations produce Fanconi anaemia phenotypes of varying severity.
Patients homozygous for null-mutations in this gene have an earlier onset of anaemia than those with mutations that produce an altered or incorrect protein. However, as most patients are 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.
Involvement in FA/BRCA pathway
In cells from Fanconi anaemia patients, FA core complex induction of FANCD2 ubiquitination is not observed, assumably a result from impaired complex formation due to the lack of a working FANCA protein. Ultimately, regardless of specific mutation, it is disruption of this FA/BRCA pathway that results in the adverse cellular and clinical phenotypes common to all FANCA-impaired Fanconi anaemia sufferers. Interactions between BRCA1 and many FANC proteins have been investigated. Amongst known FANC proteins, most evidence points for a direct interaction primarily between FANCA protein and BRCA1. Evidence from yeast two-hybrid analysis, 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.
However, as FANCA and BRCA1 undergo a constitutive interaction, this may not depend solely on detection of actual DNA damage. Instead BRCA1 protein may be more crucial in the detection of double stranded DNA breaks, or an intermediate in interstrand crosslink (ICL) repair, and rather serve to bring some of the many DNA repair proteins it interacts with to the site. One such protein would be FANCA, which in turn may serve as a docking site or anchor point at the site of ICL damage for the FA core complex. Other FANC proteins, such as FANCC, FANCE and FANCG are then assembled in this nuclear complex in the presence of FANCA as required for the action of FANCD2. This mechanic is also supported by the protein-protein interactions between BRG1 and both BRCA1 and FANCA, that serve to modulate cell-cycle kinetics alongside this. Alternatively, BRCA1 might localize FANCA to the site of DNA damage and then release it to initiate complex formation. The complex would allow 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, they are also stabilized by FANCA within the complex. For example, FANCA stabilises FANCG within the core complex, and hence mutations in FANCG are compensated for as the complex can still catalyse FANCD2-ubiquitination further downstream. FANCA 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.
Participation in haematopoiesis
FANCA is hypothesised to play a crucial role in adult (definitive) haematopoiesis during embryonic development, and is thought to be expressed in all haematopoietic sites that contribute to the formation of haematopoietic stem cells and progenitor cells (HSPCs). Most patients with a mutation develop haematological abnormalities within the first decade of life, and continue to decline until developing its most prevalent adverse affect, pancytopenia, potentially leading to death. In particular many patients develop megaloblastic anaemia around the age of 7, with this macrocytosis being the first haematological marker. 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.
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. 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 mammalian erythroid development are primitive, foetal and adult definitive. Adult, or definitive erythrocytes are the most common blood cell type and characteristically most similar across mammalian species. 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.
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. In primitive and foetal erythrocyte precursors, FANCA expression is low, and almost zero during reticulocyte formation. The marginal overall increase in the foetal stage is dwarfed by its sudden increase in expression solely during adult definitive proerythroblast formation. Here, the mean expression increases by 400% compared to foetal and primitive erythrocytes, and covers a huge margin of deviation. As FANCA is heavily implicated in controlling cellular proliferation, and often results in patients developing megaloblastic anaemia around age 7, 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 cancer and malignancies. For example, patients with homozygous null-mutations in FANCA have a markedly increased susceptibility to acute myeloid leukaemia. Furthermore, as FANC mutations in general affect DNA repair throughout the body and are predisposed to affect dynamic cell division particularly in bone marrow, it is unsurprising that patients are more likely to develop myelodysplastic syndromes (MDS) and acute myeloid leukaemia.
Knockout mice have been generated for FANCA. However, both single and double knockout murine models are healthy, viable, and do not readily show the phenotypic abnormalities typical of human Fanconi anaemia sufferers, such as haematological failure and increased susceptibility to cancers. Other markers such as infertility however still do arise. This can be seen as evidence for a lack of functional redundancy in the FANCA gene-encoded proteins. Murine models instead require induction of typical anaemic phenotypes by elevated dosing with MMC that does not affect wild-type animals, before they can be used experimentally as preclinical models for bone marrow failure and potential stem cell transplant or gene therapies.
FANCA has been shown to interact with:
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- Garcia-Higuera I, Kuang Y, Denham J, D'Andrea AD (2000). "The fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex". Blood 96 (9): 3224–30. PMID 11050007.
- McMahon LW, Walsh CE, Lambert MW (1999). "Human alpha spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex". J. Biol. Chem. 274 (46): 32904–8. doi:10.1074/jbc.274.46.32904. PMID 10551855.
- Otsuki T, Kajigaya S, Ozawa K, Liu JM (1999). "SNX5, a new member of the sorting nexin family, binds to the Fanconi anemia complementation group A protein". Biochem. Biophys. Res. Commun. 265 (3): 630–5. doi:10.1006/bbrc.1999.1731. PMID 10600472.
- McMahon LW, Sangerman J, Goodman SR, Kumaresan K, Lambert MW (2001). "Human alpha spectrin II and the FANCA, FANCC, and FANCG proteins bind to DNA containing psoralen interstrand cross-links". Biochemistry 40 (24): 7025–34. doi:10.1021/bi002917g. PMID 11401546.
- Tremblay CS.; et al. (2008). "HES1 is a novel interactor of the Fanconi anemia core complex.". Blood 112 (5): 2062–2070. doi:10.1182/blood-2008-04-152710. PMID 18550849.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Fanconi anaemia group A protein Provide feedback
No Pfam abstract.
This tab holds annotation information from the InterPro database.
InterPro entry IPR003516Fanconi anaemia (FA) [PUBMED:1641028, PUBMED:8490620, PUBMED:7929819] is a recessive inherited disease characterised by defective DNA repair. FA cells are sensitive to DNA cross-linking agents that cause chromosomal instability and cell death. The disease is manifested clinically by progressive pancytopenia, variable physical anomalies, and predisposition to malignancy [PUBMED:7929819]. Four complementation groups have been identified, designated A to D. The FA group A gene (FAA) has been cloned [PUBMED:9169126], but its function remains to be elucidated.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||15|
|Number in full:||54|
|Average length of the domain:||60.50 aa|
|Average identity of full alignment:||51 %|
|Average coverage of the sequence by the domain:||4.83 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||11|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.