AFF1

AFF1
Identifiers
Aliases	AFF1, AF4, MLLT2, PBM1, AF4/FMR2 family member 1
External IDs	OMIM: 159557; MGI: 1100819; GeneCards: AFF1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2LM0
Gene location (Human) Chr. Chromosome 4 (human) Band 4q21.3-q22.1 Start 86,935,002 bp End 87,141,039 bp
Gene location (Mouse) Chr. Chromosome 5 (mouse) Band 5 E5|5 50.45 cM Start 103,840,240 bp End 104,003,188 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Epithelium of choroid plexus renal medulla skin of hip retinal pigment epithelium tail of epididymis trabecular bone Skeletal muscle tissue of biceps brachii seminal vesicula caput epididymis glutes Top expressed in lacrimal gland ciliary body cumulus cell retinal pigment epithelium gastrula vestibular membrane of cochlear duct iris Paneth cell lobe of prostate decidua More reference expression data BioGPS n/a
Gene ontology Molecular function DNA-binding transcription factor activity protein binding double-stranded DNA binding Cellular component nucleus transcription elongation factor complex super elongation complex Biological process regulation of transcription, DNA-templated Sources:Amigo / QuickGO
Orthologs Databases NCBI: entry; OMA: entry Species Human Mouse Entrez 4299 17355 Ensembl ENSG00000172493 ENSMUSG00000029313 UniProt P51825 O88573 RefSeq (mRNA) NM_001313959 NM_001313960 NM_001166693 NM_005935 NM_001080798 NM_133919 RefSeq (protein) NP_001160165 NP_001300888 NP_001300889 NP_005926 n/a Location (UCSC) Chr 4: 86.94 – 87.14 Mb Chr 5: 103.84 – 104 Mb PubMed search
Wikidata
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AF4/FMR2 family member 1 is a protein that in humans is encoded by the AFF1 gene. At its same location was a record for a separate PBM1 gene, which has since been withdrawn and considered an alias. It was previously known as AF4 (ALL1-fused gene from chromosome 4).

The gene is a member of the AF4/FMR2 (AFF) family, a group of nuclear transcriptional activators which encourage RNA elongation. It is a component of the super elongation complex. The AFF1 protein, and to the same extent AFF4, has multiple functions but is primarily used to assemble the components of the super elongation complex by creating binding surfaces. It is recognized as a proto-oncogene: chromosomal translocations associated with leukemia can fuse this gene with others like KMT2A, producing an uncontrolled activator protein. Translocation creates the fusion protein KMT2A-AFF1 which is the primary oncogenic fusion that sets up the pre-leukemic conditions responsible for driving acute lymphoblastic leukemia.

Gene

The AFF1 gene has 23 exons and is located on the human chromosome 4 at q21 spanning approximately 206,028 base pairs long. 24 transcript variants have been identified. These variants arise through alternative splicing with each variant encoding distinct protein isoforms. These protein isoforms vary in shape and length with the most stable canonical structure being AFF1-201.

Isoforms

• 
  Image of AFF1-201 that consists of 1210 amino acids
• 
  Image of AFF1-202 that consists of 1218 amino acids
• 
  Image of AFF1-206 that consists of 406 amino acids
• 
  Image of AFF1-207 that consists of 52 amino acids
• 
  Image of AFF1-208 that consists of 137 amino acids
• 
  Image of AFF1-210 that consists of 194 amino acids

Structure

The AFF1 protein consists of approximately 1210 amino acids and contains multiple regions for protein-protein interactions. Direct, one-on-one interactions have been shown experimentally with both MLLT3 and ARFRP1 proteins, while broader datasets suggest association with numerous additional factors similarly involved in transcriptional regulation.

• 
  This is an image of the AFF1-MLLT3 interaction
• 
  This is an illustration of the AFF1 and ARFIP1 protein–protein interaction, one of two binary interactions observed through experimentation.

Function

AFF1 is a multi functional transcriptional regulator protein capable of promoting transcription elongation as well as assembling the super elongation complex. RNA Polymerase II synthesizes mRNA using the DNA template strand during the elongation step of transcription with the support of AFF1 and the super elongation complex. In this complex AFF1 brings with it the P-TEFb protein, which stimulates RNA Polymerase II into transitioning from promoter-proximal pausing to productive elongation. AFF1 also brings the ELL elongation factor enzyme which increases the catalytic rate of RNA Polymerase II transcription, helping produce rapid gene expression. In this way AFF1 acts as a scaffold protein by assembling and stabilizing the super elongation complex to promote efficient transcription elongation.

Clinical signficance

AFF family proteins like AFF1 are critical for the stability and function of the super elongation complex. Chromosomal translocation with Histone-lysine N-methyltransferase 2A, also known as mixed-lineage leukemia 1 (MLL1), is associated with acute lymphoblastic leukemia. KMT2A–AFF1, or MLL-AFF1, is one of the fused proteins responsible for misregulation of transcription elongation. The most common translocations of these proteins are KMT2A-AFF1 and its reciprocal AFF1-KMT2A, however AFF1-KMT2A is not the main driver of acute lymphoblastic leukemia. Although AFF1-KMT2A is capable of setting up pre-leukemic conditions, this reciprocal protein fusion later becomes dispensable. The canonical oncogenic protein fusion is KMT2A-AFF1 which has been shown through gene-knockdown experimentation.

The dangerous pre-leukemic state caused by the KMT2A-AFF1 fusion is dependent on age because this fusion can lead to the misregulation of transcription elongation in fetal and embryonic hematopoietic stem cells. In contrast, the same fusion when induced in adult mice caused less hematopoietic stem cell proliferation.

AFF1 is also implicated in the transcriptional regulation of HIV and other viruses because its role in the super elongation complex is exploitable, enhancing viral gene expression through transcription elongation. In order to hijack the super elongation complex, HIV produces the Tat protein to recruit P-TEFb which ends up significantly boosting viral gene expression. Tat also has an affinity for super elongation complexes containing AFF1 and AFF4 proteins. AFF1 and AFF4 scaffolding proteins create more stable binding surface for both Tat and P-TEFb proteins, because AFF family proteins reshape the surface of P-TEFb when present in the super elongation complex.

References

External links

• Human AFF1 genome location and AFF1 gene details page in the UCSC Genome Browser.

Further reading