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.[3]
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.[4][5]
DNA strand breaks
Ataxia oculomotor apraxia-1 is a neurological disorder caused by mutations in the APTX gene that encodes aprataxin.[6] The neurological disorder appears to be caused by the gradual accumulation of unrepaired DNA strand breaks resulting from abortive DNA ligation events.[6]
Premature aging
Aptx−/− mutant mice have been generated, but they lack an obvious phenotype.[6] Another mouse model was generated in which a mutation of superoxide dismutase I (SOD1) is expressed in an Aptx−/− mouse.[7] 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 [7] (see DNA damage theory of aging).
↑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. PMID11586299.
↑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. PMID11586300.
↑ 6.06.16.2Ahel 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. PMID16964241.
↑ 7.07.1Carroll 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. PMID25274775.
↑ 8.08.1Date 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. PMID15555565.
↑ 9.09.19.2Gueven 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. PMID15044383.
↑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. PMID15380105.
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. PMID3239952.
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. PMID12196655.
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. PMID14506070.
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. PMID14534929.
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. PMID14702039.
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. PMID14755728.
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. PMID15044383.
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. PMID15164193.
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. PMID15276230.
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. PMID15380105.