7t8c

Structural highlights

Disease

PEO1_HUMAN Mitochondrial DNA depletion syndrome, hepatocerebrorenal form;Infantile-onset spinocerebellar ataxia;Perrault syndrome;Autosomal dominant progressive external ophthalmoplegia;Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

PEO1_HUMAN Mitochondrial helicase involved in mtDNA replication and repair (PubMed:12975372, PubMed:15167897, PubMed:17324440, PubMed:18039713, PubMed:18971204, PubMed:25824949, PubMed:26887820, PubMed:27226550). Might have a role in mtDNA repair (PubMed:27226550). Has DNA strand separation activity needed to form a processive replication fork for leading strand synthesis which is catalyzed by the formation of a replisome complex with POLG and mtSDB (PubMed:12975372, PubMed:15167897, PubMed:18039713, PubMed:22383523, PubMed:26887820, PubMed:27226550). Preferentially unwinds DNA substrates with pre-existing 5'-and 3'- single-stranded tails but is also active on a 5'- flap substrate (PubMed:12975372, PubMed:15167897, PubMed:18039713, PubMed:22383523, PubMed:26887820, PubMed:27226550). Can dissociate the invading strand of immobile or mobile D-loop DNA structures irrespective of the single strand polarity of the third strand (PubMed:27226550). In addition to its DNA strand separation activity, also has DNA strand annealing, DNA strand-exchange and DNA branch migration activities (PubMed:22383523, PubMed:26887820, PubMed:27226550).^{[1] [2] [3] [4] [5] [6] [7] [8] [9]} Lack DNA unwinding and ATP hydrolysis activities (PubMed:18039713). Does not bind single-stranded or double-stranded DNA (PubMed:18039713).^[10]

References

1. ↑ Korhonen JA, Gaspari M, Falkenberg M. TWINKLE Has 5' -> 3' DNA helicase activity and is specifically stimulated by mitochondrial single-stranded DNA-binding protein. J Biol Chem. 2003 Dec 5;278(49):48627-32. doi: 10.1074/jbc.M306981200. Epub 2003 , Sep 15. PMID:12975372 doi:http://dx.doi.org/10.1074/jbc.M306981200
2. ↑ Korhonen JA, Pham XH, Pellegrini M, Falkenberg M. Reconstitution of a minimal mtDNA replisome in vitro. EMBO J. 2004 Jun 16;23(12):2423-9. doi: 10.1038/sj.emboj.7600257. Epub 2004 May, 27. PMID:15167897 doi:http://dx.doi.org/10.1038/sj.emboj.7600257
3. ↑ Ziebarth TD, Farr CL, Kaguni LS. Modular architecture of the hexameric human mitochondrial DNA helicase. J Mol Biol. 2007 Apr 13;367(5):1382-91. doi: 10.1016/j.jmb.2007.01.079. Epub 2007, Feb 7. PMID:17324440 doi:http://dx.doi.org/10.1016/j.jmb.2007.01.079
4. ↑ Farge G, Holmlund T, Khvorostova J, Rofougaran R, Hofer A, Falkenberg M. The N-terminal domain of TWINKLE contributes to single-stranded DNA binding and DNA helicase activities. Nucleic Acids Res. 2008 Feb;36(2):393-403. doi: 10.1093/nar/gkm1025. Epub 2007, Nov 26. PMID:18039713 doi:http://dx.doi.org/10.1093/nar/gkm1025
5. ↑ Goffart S, Cooper HM, Tyynismaa H, Wanrooij S, Suomalainen A, Spelbrink JN. Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling. Hum Mol Genet. 2009 Jan 15;18(2):328-40. doi: 10.1093/hmg/ddn359. Epub 2008 Oct, 29. PMID:18971204 doi:http://dx.doi.org/10.1093/hmg/ddn359
6. ↑ Sen D, Nandakumar D, Tang GQ, Patel SS. Human mitochondrial DNA helicase TWINKLE is both an unwinding and annealing helicase. J Biol Chem. 2012 Apr 27;287(18):14545-56. doi: 10.1074/jbc.M111.309468. Epub, 2012 Mar 1. PMID:22383523 doi:http://dx.doi.org/10.1074/jbc.M111.309468
7. ↑ Fernandez-Millan P, Lazaro M, Cansiz-Arda S, Gerhold JM, Rajala N, Schmitz CA, Silva-Espina C, Gil D, Bernado P, Valle M, Spelbrink JN, Sola M. The hexameric structure of the human mitochondrial replicative helicase Twinkle. Nucleic Acids Res. 2015 Apr 30;43(8):4284-95. doi: 10.1093/nar/gkv189. Epub 2015 , Mar 30. PMID:25824949 doi:http://dx.doi.org/10.1093/nar/gkv189
8. ↑ Sen D, Patel G, Patel SS. Homologous DNA strand exchange activity of the human mitochondrial DNA helicase TWINKLE. Nucleic Acids Res. 2016 May 19;44(9):4200-10. doi: 10.1093/nar/gkw098. Epub 2016 , Feb 16. PMID:26887820 doi:http://dx.doi.org/10.1093/nar/gkw098
9. ↑ Khan I, Crouch JD, Bharti SK, Sommers JA, Carney SM, Yakubovskaya E, Garcia-Diaz M, Trakselis MA, Brosh RM Jr. Biochemical Characterization of the Human Mitochondrial Replicative Twinkle Helicase: SUBSTRATE SPECIFICITY, DNA BRANCH MIGRATION, AND ABILITY TO OVERCOME BLOCKADES TO DNA UNWINDING. J Biol Chem. 2016 Jul 1;291(27):14324-14339. doi: 10.1074/jbc.M115.712026. Epub, 2016 May 11. PMID:27226550 doi:http://dx.doi.org/10.1074/jbc.M115.712026
10. ↑ Farge G, Holmlund T, Khvorostova J, Rofougaran R, Hofer A, Falkenberg M. The N-terminal domain of TWINKLE contributes to single-stranded DNA binding and DNA helicase activities. Nucleic Acids Res. 2008 Feb;36(2):393-403. doi: 10.1093/nar/gkm1025. Epub 2007, Nov 26. PMID:18039713 doi:http://dx.doi.org/10.1093/nar/gkm1025