aprataxin; forkhead-associated domain histidine-triad like protein; FHA-HIT (APTX, AXA1)

Function

• DNA-binding protein involved in:
  • single-strand DNA break repair
  • double-strand DNA break repair
  • base excision repair
• resolves abortive DNA ligation intermediates formed either at base excision sites, or when DNA ligases attempt to repair non-ligatable breaks induced by reactive oxygen species
• catalyzes the release of adenylate groups covalently linked to 5'-phosphate termini, resulting in the production of 5'-phosphate termini that can be efficiently rejoined
• also able to hydrolyze adenosine 5'-monophosphoramidate (AMP-NH(2)) & diadenosine tetraphosphate (appppA), but with lower catalytic activity
• interacts with single-strand break repair proteins XRCC1, XRCC4, ADPRT & p53/TP53
• interacts with NCL
• interacts (via FHA- like domain) with MDC1 (phosphorylated)

Kinetic parameters:

• KM=18 uM for appppA
• KM=837.5 uM for AMP-NH(2)

Structure

• the histidine triad, also called HIT motif, forms part of the binding loop for the alpha-phosphate of purine mononucleotide
• the FHA-like domain mediates interaction with NCL, XRCC1 & XRCC4
• the HIT domain is required for enzymatic activity
• the C2H2-type Zn+2 finger mediates DNA-binding
• contains 1 C2H2-type Zn+2 finger
• contains 1 FHA-like domain
• contains 1 HIT domain

Compartment

• nucleus, nucleoplasm, nucleolus
• upon genotoxic stress, colocalizes with XRCC1 at sites of DNA damage
• colocalizes with MDC1 at sites of DNA double-strand breaks
• interaction with NCL is required for nucleolar localization

Alternative splicing

• named isoforms=11
• at least one isoformmay be an aberrant isoform present in cancer cell lines

Expression

• widely expressed
• in brain, expressed in the posterior cortex, cerebellum, hippocampus & olfactory bulb
• isoform 1 is highly expressed in the cerebral cortex & cerebellum, compared to isoform 2

Pathology

• defects in APTX are the cause of ataxia-oculomotor apraxia syndrome
• defects in APTX are a cause of coenzyme Q10 deficiency

More general terms

• nuclear protein
• C2H2 type zinc finger protein

Additional terms

• ataxia-oculomotor apraxia syndrome; ataxia-telangiectasia-like syndrome; cerebellar ataxia early-onset with apraxia & hypoalbuminemia (EOCA-HA, AOA1)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=54840
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:54840
• OMIM: https://mirror.omim.org/entry/208920
• OMIM: https://mirror.omim.org/entry/606350
• OMIM: https://mirror.omim.org/entry/607426
• UniProt: http://www.uniprot.org/uniprot/Q7Z2E3.html