Aprataxin

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

APTX
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3KT9, 4NDF, 4NDG, 4NDH, 4NDI
Identifiers
Aliases	APTX, AOA, AOA1, AXA1, EAOH, EOAHA, FHA-HIT, aprataxin
External IDs	OMIM: 606350 MGI: 1913658 HomoloGene: 41634 GeneCards: APTX
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9p21.1 Start 32,972,606 bp[1] End 33,025,168 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4|4 A5 Start 40,682,382 bp[2] End 40,703,194 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA binding • protein N-terminus binding • polynucleotide 3'-phosphatase activity • chromatin binding • metal ion binding • damaged DNA binding • phosphoprotein binding • GO:0001948 protein binding • phosphoglycolate phosphatase activity • catalytic activity • double-stranded RNA binding • double-stranded DNA binding • hydrolase activity • DNA 5'-adenosine monophosphate hydrolase activity • nucleic acid binding • DNA-3'-diphospho-5'-guanosine diphosphatase • single-stranded DNA binding • mismatched DNA binding • single-strand break-containing DNA binding Cellular component • cytoplasm • nuclear chromatin • chromatin • nucleolus • cell nucleus • nucleoplasm Biological process • regulation of protein stability • cellular response to DNA damage stimulus • DNA ligation • double-strand break repair • response to hydrogen peroxide • DNA repair • polynucleotide 3' dephosphorylation • nucleic acid phosphodiester bond hydrolysis • single strand break repair • dephosphorylation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	54840	66408
Ensembl	ENSG00000137074	ENSMUSG00000028411
UniProt	Q7Z2E3	Q7TQC5
RefSeq (mRNA)	NM_001195248 NM_001195249 NM_001195250 NM_001195251 NM_001195252 NM_001195254 NM_017692 NM_175069 NM_175072 NM_175073	NM_001025444 NM_001025445 NM_025545
RefSeq (protein)	NP_001182177 NP_001182178 NP_001182179 NP_001182180 NP_001182181 NP_001182183 NP_778239 NP_778243 NP_001355924 NP_001355925 NP_001355926 NP_001355927 NP_001355928 NP_001355929 NP_001355930 NP_001355931 NP_001355932 NP_001355933 NP_001355934 NP_001355935 NP_001357598 NP_001357599 NP_001357602	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

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:

• PARP1,[12][13]
• P53,[13]
• XRCC1,[12][13] and
• XRCC4.[14]

References

1. GRCh38: Ensembl release 89: ENSG00000137074 - Ensembl, May 2017
2. 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. "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. 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. doi:10.1038/nature05164. PMID 16964241. S2CID 4431045.
11. 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. 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. 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.

Further reading

• Aicardi J, Barbosa C, Andermann E, et al. (1989). "Ataxia-ocular motor apraxia: a syndrome mimicking ataxia-telangiectasia". Ann. Neurol. 24 (4): 497–502. doi:10.1002/ana.410240404. PMID 3239952. S2CID 45836910.
• Gascon GG, Abdo N, Sigut D, et al. (1995). "Ataxia-oculomotor apraxia syndrome". J. Child Neurol. 10 (2): 118–22. doi:10.1177/088307389501000210. PMID 7782601. S2CID 26080242.
• Hannan MA, Sigut D, Waghray M, Gascon GG (1995). "Ataxia-ocular motor apraxia syndrome: an investigation of cellular radiosensitivity of patients and their families". J. Med. Genet. 31 (12): 953–6. doi:10.1136/jmg.31.12.953. PMC 1016697. PMID 7891378.
• Moreira MC, Barbot C, Tachi N, et al. (2001). "Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity". Am. J. Hum. Genet. 68 (2): 501–8. doi:10.1086/318191. PMC 1235299. PMID 11170899.
• Brenner C (2002). "Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases". Biochemistry. 41 (29): 9003–14. doi:10.1021/bi025942q. PMC 2571077. PMID 12119013.
• Shimazaki H, Takiyama Y, Sakoe K, et al. (2002). "Early-onset ataxia with ocular motor apraxia and hypoalbuminemia: the aprataxin gene mutations". Neurology. 59 (4): 590–5. doi:10.1212/wnl.59.4.590. PMID 12196655. S2CID 19576330.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Tranchant C, Fleury M, Moreira MC, et al. (2004). "Phenotypic variability of aprataxin gene mutations". Neurology. 60 (5): 868–70. doi:10.1212/01.wnl.0000048562.88536.a4. PMID 12629250. S2CID 29358633.
• Le Ber I, Moreira MC, Rivaud-Péchoux S, et al. (2003). "Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies". Brain. 126 (Pt 12): 2761–72. doi:10.1093/brain/awg283. PMID 14506070.
• Sekijima Y, Hashimoto T, Onodera O, et al. (2004). "Severe generalized dystonia as a presentation of a patient with aprataxin gene mutation". Mov. Disord. 18 (10): 1198–200. doi:10.1002/mds.10526. PMID 14534929. S2CID 28225863.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Sano Y, Date H, Igarashi S, et al. (2004). "Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein". Ann. Neurol. 55 (2): 241–9. doi:10.1002/ana.10808. PMID 14755728. S2CID 25338143.
• Gueven N, Becherel OJ, Kijas AW, et al. (2004). "Aprataxin, a novel protein that protects against genotoxic stress". Hum. Mol. Genet. 13 (10): 1081–93. doi:10.1093/hmg/ddh122. PMID 15044383.
• Humphray SJ, Oliver K, Hunt AR, et al. (2004). "DNA sequence and analysis of human chromosome 9". Nature. 429 (6990): 369–74. doi:10.1038/nature02465. PMC 2734081. PMID 15164053.
• Habeck M, Zühlke C, Bentele KH, et al. (2004). "Aprataxin mutations are a rare cause of early onset ataxia in Germany". J. Neurol. 251 (5): 591–4. doi:10.1007/s00415-004-0374-7. PMID 15164193. S2CID 20280677.
• Hirano M, Nishiwaki T, Kariya S, et al. (2004). "Novel splice variants increase molecular diversity of aprataxin, the gene responsible for early-onset ataxia with ocular motor apraxia and hypoalbuminemia". Neurosci. Lett. 366 (2): 120–5. doi:10.1016/j.neulet.2004.05.034. PMID 15276230. S2CID 37647769.
• Amouri R, Moreira MC, Zouari M, et al. (2005). "Aprataxin gene mutations in Tunisian families". Neurology. 63 (5): 928–9. doi:10.1212/01.wnl.0000137044.06573.46. PMID 15365154. S2CID 41637052.
• Clements PM, Breslin C, Deeks ED, et al. (2005). "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.

External links

• GeneReviews/NCBI/NIH/UW entry on Ataxia with Oculomotor Apraxia Type 1
• OMIM entries on Ataxia with Oculomotor Apraxia Type 1
• Human APTX genome location and APTX gene details page in the UCSC Genome Browser.