Aprataxin

Last updated
APTX
APTX .png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases APTX , AOA, AOA1, AXA1, EAOH, EOAHA, FHA-HIT, aprataxin
External IDs OMIM: 606350 MGI: 1913658 HomoloGene: 41634 GeneCards: APTX
Orthologs
SpeciesHumanMouse
Entrez

54840

66408

Ensembl

ENSG00000137074

ENSMUSG00000028411

UniProt

Q7Z2E3

Q7TQC5

RefSeq (mRNA)

NM_001025444
NM_001025445
NM_025545

RefSeq (protein)

NP_001020615
NP_001020616
NP_079821

Location (UCSC) Chr 9: 32.97 – 33.03 Mb Chr 4: 40.68 – 40.7 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Aprataxin is a protein that in humans is encoded by the APTX gene. [5] [6] [7]

This gene encodes a member of the histidine triad (HIT) superfamily, some of which have nucleotide-binding and diadenosine polyphosphate hydrolase activities. The encoded protein may play a role in single-stranded DNA repair. Mutations in this gene have been associated with ataxia–ocular apraxia. Multiple transcript variants encoding distinct isoforms have been identified for this gene, however, the full length nature of some variants has not been determined. [7]

Function

Aprataxin removes AMP from DNA ends following abortive ligation attempts by DNA Ligase IV during non-homologous end joining, thereby permitting subsequent attempts at ligation. [8] [9]

DNA strand breaks

Ataxia oculomotor apraxia-1 is a neurological disorder caused by mutations in the APTX gene that encodes aprataxin. [10] The neurological disorder appears to be caused by the gradual accumulation of unrepaired DNA strand breaks resulting from abortive DNA ligation events. [10]

Premature aging

Aptx−/− mutant mice have been generated, but they lack an obvious phenotype. [10] Another mouse model was generated in which a mutation of superoxide dismutase I (SOD1) is expressed in an Aptx−/− mouse. [11] The SOD1 mutation causes a reduction in transcription recovery following oxidative stress. These mice showed accelerated cellular senescence. This study also demonstrated a protective role of Aptx in vivo and suggested that the loss of Aptx function results in progressive accumulation of DNA breaks in the nervous system, triggering hallmarks of systemic premature aging [11] (see DNA damage theory of aging).

Interactions

Aprataxin has been shown to interact with:

Related Research Articles

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Oculomotor apraxia (OMA) is the absence or defect of controlled, voluntary, and purposeful eye movement. It was first described in 1952 by the American ophthalmologist David Glendenning Cogan. People with this condition have difficulty moving their eyes horizontally and moving them quickly. The main difficulty is in saccade initiation, but there is also impaired cancellation of the vestibulo-ocular reflex. Patients have to turn their head in order to compensate for the lack of eye movement initiation in order to follow an object or see objects in their peripheral vision, but they often exceed their target. There is controversy regarding whether OMA should be considered an apraxia, since apraxia is the inability to perform a learned or skilled motor action to command, and saccade initiation is neither a learned nor a skilled action.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000137074 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028411 - 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. ↑ Date H, Onodera O, Tanaka H, Iwabuchi K, Uekawa K, Igarashi S, Koike R, Hiroi T, Yuasa T, Awaya Y, Sakai T, Takahashi T, Nagatomo H, Sekijima Y, Kawachi I, Takiyama Y, Nishizawa M, Fukuhara N, Saito K, Sugano S, Tsuji S (Oct 2001). "Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene". Nat Genet. 29 (2): 184–8. doi:10.1038/ng1001-184. PMID   11586299. S2CID   25665707.
  6. ↑ Moreira MC, Barbot C, Tachi N, Kozuka N, Uchida E, Gibson T, Mendonca P, Costa M, Barros J, Yanagisawa T, Watanabe M, Ikeda Y, Aoki M, Nagata T, Coutinho P, Sequeiros J, Koenig M (Oct 2001). "The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin". Nat Genet. 29 (2): 189–93. doi:10.1038/ng1001-189. PMID   11586300. S2CID   23001321.
  7. 1 2 "Entrez Gene: APTX aprataxin".
  8. ↑ Rass U, Ahel I, West SC (December 2008). "Molecular mechanism of DNA deadenylation by the neurological disease protein aprataxin". J. Biol. Chem. 283 (49): 33994–4001. doi: 10.1074/jbc.M807124200 . PMC   2662222 . PMID   18836178.
  9. ↑ Reynolds JJ, El-Khamisy SF, Katyal S, Clements P, McKinnon PJ, Caldecott KW (March 2009). "Defective DNA ligation during short-patch single-strand break repair in ataxia oculomotor apraxia 1". Mol. Cell. Biol. 29 (5): 1354–62. doi:10.1128/MCB.01471-08. PMC   2643831 . PMID   19103743.
  10. 1 2 3 Ahel I, Rass U, El-Khamisy SF, Katyal S, Clements PM, McKinnon PJ, Caldecott KW, West SC (2006). "The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates". Nature. 443 (7112): 713–6. Bibcode:2006Natur.443..713A. doi:10.1038/nature05164. PMID   16964241. S2CID   4431045.
  11. 1 2 Carroll J, Page TK, Chiang SC, Kalmar B, Bode D, Greensmith L, Mckinnon PJ, Thorpe JR, Hafezparast M, El-Khamisy SF (2015). "Expression of a pathogenic mutation of SOD1 sensitizes aprataxin-deficient cells and mice to oxidative stress and triggers hallmarks of premature ageing". Hum. Mol. Genet. 24 (3): 828–40. doi:10.1093/hmg/ddu500. PMC   4291253 . PMID   25274775.
  12. 1 2 Date H, Igarashi S, Sano Y, Takahashi T, Takahashi T, Takano H, Tsuji S, Nishizawa M, Onodera O (December 2004). "The FHA domain of aprataxin interacts with the C-terminal region of XRCC1". Biochem. Biophys. Res. Commun. 325 (4): 1279–85. doi:10.1016/j.bbrc.2004.10.162. PMID   15555565.
  13. 1 2 3 Gueven N, Becherel OJ, Kijas AW, Chen P, Howe O, Rudolph JH, Gatti R, Date H, Onodera O, Taucher-Scholz G, Lavin MF (May 2004). "Aprataxin, a novel protein that protects against genotoxic stress". Hum. Mol. Genet. 13 (10): 1081–93. doi: 10.1093/hmg/ddh122 . PMID   15044383.
  14. ↑ Clements PM, Breslin C, Deeks ED, Byrd PJ, Ju L, Bieganowski P, Brenner C, Moreira MC, Taylor AM, Caldecott KW (November 2004). "The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4". DNA Repair (Amst.). 3 (11): 1493–502. doi:10.1016/j.dnarep.2004.06.017. PMID   15380105.

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