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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
Related
ataxia-oculomotor apraxia syndrome; ataxia-telangiectasia-like syndrome; cerebellar ataxia early-onset with apraxia & hypoalbuminemia (EOCA-HA, AOA1)
General
C2H2 type zinc finger protein
nuclear protein
Properties
SIZE: entity length = 356 aa
MW = 41 kD
COMPARTMENT: cell nucleus
MOTIF: Interactions with ADPRT & NCL {1-110}
MOTIF: forkhead-associated (FHA) domain {38-87}
nuclear translocation signal {126-131}
HIstidine Triad (HIT domain) {182-287}
MOTIF: Histidine triad {272-276}
histidine residue {H274}
Zn finger C2H2-type
SITE: 331-353
EFFECTOR-BOUND: Zn+2
Database Correlations
OMIM correlations
MORBIDMAP 606350
UniProt Q7Z2E3
Entrez Gene 54840
Kegg hsa:54840
References
- UniProt :accession Q7Z2E3
- GeneReviews
http://www.ncbi.nlm.nih.gov/sites/genetests/lab/gene/APTX