View source for PNKP

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Bifunctional polynucleotide phosphatase/kinase''' is an [[enzyme]] that in humans is encoded by the ''PNKP'' [[gene]].<ref name="pmid10446192">{{cite journal | vauthors = Jilani A, Ramotar D, Slack C, Ong C, Yang XM, Scherer SW, Lasko DD | title = Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3'-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage | journal = J. Biol. Chem. | volume = 274 | issue = 34 | pages = 24176–86  | date = September 1999 | pmid = 10446192 | doi = 10.1074/jbc.274.34.24176 | doi-access = free }}</ref><ref name="pmid10446193">{{cite journal | vauthors = Karimi-Busheri F, Daly G, Robins P, Canas B, Pappin DJ, Sgouros J, Miller GG, Fakhrai H, Davis EM, Le Beau MM, Weinfeld M | title = Molecular characterization of a human DNA kinase | journal = J. Biol. Chem. | volume = 274 | issue = 34 | pages = 24187–94  | date = September 1999 | pmid = 10446193 | doi = 10.1074/jbc.274.34.24187 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: PNKP polynucleotide kinase 3'-phosphatase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11284}}</ref> A detailed structural study of the crystallized mouse protein examined both the 5´-polynucleotide kinase and 3’-polynucleotide phosphatase activities.<ref>{{Cite journal|last1=Garces|first1=Fernando|last2=Pearl|first2=Laurence H.|last3=Oliver|first3=Antony W.|date=November 2011|title=The Structural Basis for Substrate Recognition by Mammalian Polynucleotide Kinase 3′ Phosphatase|url= |journal=Molecular Cell|language=en|volume=44|issue=3|pages=385–396|doi=10.1016/j.molcel.2011.08.036|pmc=4820033|pmid=22055185}}</ref> Additional features of the peptide sequence include a forkhead association (FHA) domain, ATP binding site and nuclear and mitochondrial localization sequences.
== Interactions ==
PNKP has been shown to [[Protein-protein interaction|interact]] with [[DNA polymerase beta]]<ref name=pmid11163244>{{cite journal | vauthors = Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW | title = XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair | journal = Cell | volume = 104 | issue = 1 | pages = 107–17  | date = January 2001 | pmid = 11163244 | doi = 10.1016/S0092-8674(01)00195-7 | s2cid = 1487128 | doi-access = free }}</ref> and [[XRCC1]].<ref name=pmid11163244/><ref name=pmid17353931>{{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Mol. Syst. Biol. | volume = 3 | issue = 1 | pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 }}</ref>
== Role in neurologic disease==
The human gene encoding PNKP was observed to be mutated in patients<ref>{{Cite journal|last1=Dumitrache|first1=Lavinia C.|last2=McKinnon|first2=Peter J.|date=2017|title=Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease|journal=Mechanisms of Ageing and Development|language=en|volume=161|issue=Pt A|pages=121–129|doi=10.1016/j.mad.2016.04.009|pmc=5161711|pmid=27125728}}</ref><ref>{{Cite journal|last1=Shen|first1=Jun|last2=Gilmore|first2=Edward C|last3=Marshall|first3=Christine A|last4=Haddadin|first4=Mary|last5=Reynolds|first5=John J|last6=Eyaid|first6=Wafaa|last7=Bodell|first7=Adria|last8=Barry|first8=Brenda|last9=Gleason|first9=Danielle|last10=Allen|first10=Kathryn|last11=Ganesh|first11=Vijay S|date=2010|title=Mutations in PNKP cause microcephaly, seizures and defects in DNA repair|journal=Nat Genet|language=en|volume=42|issue=3|pages=245–249|doi=10.1038/ng.526|issn=1061-4036|pmc=2835984|pmid=20118933}}</ref><ref>{{Cite journal|last1=Issa|first1=Lina|last2=Mueller|first2=Katrin|last3=Seufert|first3=Katja|last4=Kraemer|first4=Nadine|last5=Rosenkotter|first5=Henning|last6=Ninnemann|first6=Olaf|last7=Buob|first7=Michael|last8=Kaindl|first8=Angela M|last9=Morris-Rosendahl|first9=Deborah J|date=2013|title=Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation|journal=Orphanet Journal of Rare Diseases|language=en|volume=8|issue=1|pages=59|doi=10.1186/1750-1172-8-59|issn=1750-1172|pmc=3639195|pmid=23587236 |doi-access=free }}</ref><ref>{{Cite journal|last1=Kalasova|first1=Ilona|last2=Hanzlikova|first2=Hana|last3=Gupta|first3=Neerja|last4=Li|first4=Yun|last5=Altmüller|first5=Janine|last6=Reynolds|first6=John J.|last7=Stewart|first7=Grant S.|last8=Wollnik|first8=Bernd|last9=Yigit|first9=Gökhan|last10=Caldecott|first10=Keith W.|date=2019|title=Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ|journal=Neurol Genet|language=en|volume=5|issue=2|pages=e320|doi=10.1212/NXG.0000000000000320|issn=2376-7839|pmc=6454307|pmid=31041400}}</ref> with microcephaly, seizures and defects in DNA repair. A type of recessive ataxia is also associated with PNKP mutations.<ref>{{Cite journal|last1=Bras|first1=Jose|last2=Alonso|first2=Isabel|last3=Barbot|first3=Clara|last4=Costa|first4=Maria Manuela|last5=Darwent|first5=Lee|last6=Orme|first6=Tatiana|last7=Sequeiros|first7=Jorge|last8=Hardy|first8=John|last9=Coutinho|first9=Paula|last10=Guerreiro|first10=Rita|date=2015|title=Mutations in PNKP Cause Recessive Ataxia with Oculomotor Apraxia Type 4|journal=The American Journal of Human Genetics|language=en|volume=96|issue=3|pages=474–479|doi=10.1016/j.ajhg.2015.01.005|pmc=4375449|pmid=25728773}}</ref> There are also newly characterized pathological variants of PNKP.<ref>{{Cite journal|last1=Gatti|first1=Marta|last2=Magri|first2=Stefania|last3=Nanetti|first3=Lorenzo|last4=Sarto|first4=Elisa|last5=Di Bella|first5=Daniela|last6=Salsano|first6=Ettore|last7=Pantaleoni|first7=Chiara|last8=Mariotti|first8=Caterina|last9=Taroni|first9=Franco|date=2019|title=From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations|journal=American Journal of Medical Genetics Part A|language=en|volume=179|issue=11|pages=2277–2283|doi=10.1002/ajmg.a.61339|pmid=31436889|s2cid=201275630|issn=1552-4825}}</ref> Model organisms such as mice and ''[[Drosophila]]'' have been used to generate further insights.<ref>{{Cite journal|last1=Shimada|first1=Mikio|last2=Dumitrache|first2=Lavinia C|last3=Russell|first3=Helen R|last4=McKinnon|first4=Peter J|date=2015|title=Polynucleotide kinase–phosphatase enables neurogenesis via multiple DNA repair pathways to maintain genome stability|journal=The EMBO Journal|language=en|volume=34|issue=19|pages=2465–2480|doi=10.15252/embj.201591363|issn=0261-4189|pmc=4601665|pmid=26290337}}</ref><ref>{{Cite journal|last1=Chakraborty|first1=Anirban|last2=Tapryal|first2=Nisha|last3=Venkova|first3=Tatiana|last4=Mitra|first4=Joy|last5=Vasquez|first5=Velmarini|last6=Sarker|first6=Altaf H.|last7=Duarte-Silva|first7=Sara|last8=Huai|first8=Weihan|last9=Ashizawa|first9=Tetsuo|last10=Ghosh|first10=Gourisankar|last11=Maciel|first11=Patricia|date=2020-04-07|title=Deficiency in classical nonhomologous end-joining–mediated repair of transcribed genes is linked to SCA3 pathogenesis|journal=Proceedings of the National Academy of Sciences|language=en|volume=117|issue=14|pages=8154–8165|doi=10.1073/pnas.1917280117|pmid=32205441|pmc=7148577|bibcode=2020PNAS..117.8154C |issn=0027-8424|doi-access=free }}</ref>
== References ==
{{reflist}}
== Further reading ==
{{refbegin | 2}}
* {{cite journal | vauthors = Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, Weinfeld M, Caldecott KW | title = XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair | journal = Cell | volume = 104 | issue = 1 | pages = 107–17 | year = 2001 | pmid = 11163244 | doi = 10.1016/S0092-8674(01)00195-7 | s2cid = 1487128 | doi-access = free }}
* {{cite journal | vauthors = Chappell C, Hanakahi LA, Karimi-Busheri F, Weinfeld M, West SC | title = Involvement of human polynucleotide kinase in double-strand break repair by non-homologous end joining | journal = EMBO J. | volume = 21 | issue = 11 | pages = 2827–32 | year = 2002 | pmid = 12032095 | pmc = 126026 | doi = 10.1093/emboj/21.11.2827 }}
* {{cite journal | vauthors = Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, Marra MA | title = Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 26 | pages = 16899–903 | year = 2002 | pmid = 12477932 | pmc = 139241 | doi = 10.1073/pnas.242603899 | bibcode = 2002PNAS...9916899M | doi-access = free }}
* {{cite journal | vauthors = Mani RS, Karimi-Busheri F, Fanta M, Cass CE, Weinfeld M | title = Spectroscopic studies of DNA and ATP binding to human polynucleotide kinase: evidence for a ternary complex | journal = Biochemistry | volume = 42 | issue = 41 | pages = 12077–84 | year = 2003 | pmid = 14556639 | doi = 10.1021/bi030127b }}
* {{cite journal | vauthors = Loizou JI, El-Khamisy SF, Zlatanou A, Moore DJ, Chan DW, Qin J, Sarno S, Meggio F, Pinna LA, Caldecott KW | title = The protein kinase CK2 facilitates repair of chromosomal DNA single-strand breaks | journal = Cell | volume = 117 | issue = 1 | pages = 17–28 | year = 2004 | pmid = 15066279 | doi = 10.1016/S0092-8674(04)00206-5 | s2cid = 8592154 | doi-access = free }}
* {{cite journal | vauthors = Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM | title = Functional proteomics mapping of a human signaling pathway | journal = Genome Res. | volume = 14 | issue = 7 | pages = 1324–32 | year = 2004 | pmid = 15231748 | pmc = 442148 | doi = 10.1101/gr.2334104 }}
* {{cite journal | vauthors = Wiederhold L, Leppard JB, Kedar P, Karimi-Busheri F, Rasouli-Nia A, Weinfeld M, Tomkinson AE, Izumi T, Prasad R, Wilson SH, Mitra S, Hazra TK | title = AP endonuclease-independent DNA base excision repair in human cells | journal = Mol. Cell | volume = 15 | issue = 2 | pages = 209–20 | year = 2004 | pmid = 15260972 | doi = 10.1016/j.molcel.2004.06.003 | doi-access = free }}
* {{cite journal | vauthors = Koch CA, Agyei R, Galicia S, Metalnikov P, O'Donnell P, Starostine A, Weinfeld M, Durocher D | title = Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV | journal = EMBO J. | volume = 23 | issue = 19 | pages = 3874–85 | year = 2004 | pmid = 15385968 | pmc = 522785 | doi = 10.1038/sj.emboj.7600375 }}
* {{cite journal | vauthors = Andersen JS, Lam YW, Leung AK, Ong SE, Lyon CE, Lamond AI, Mann M | title = Nucleolar proteome dynamics | journal = Nature | volume = 433 | issue = 7021 | pages = 77–83 | year = 2005 | pmid = 15635413 | doi = 10.1038/nature03207 | bibcode = 2005Natur.433...77A | s2cid = 4344740 }}
* {{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | year = 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R | s2cid = 4427026 }}
* {{cite journal | vauthors = Audebert M, Salles B, Weinfeld M, Calsou P | title = Involvement of polynucleotide kinase in a poly(ADP-ribose) polymerase-1-dependent DNA double-strand breaks rejoining pathway | journal = J. Mol. Biol. | volume = 356 | issue = 2 | pages = 257–65 | year = 2006 | pmid = 16364363 | doi = 10.1016/j.jmb.2005.11.028 }}
* {{cite journal | vauthors = Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M | title = Global, in vivo, and site-specific phosphorylation dynamics in signaling networks | journal = Cell | volume = 127 | issue = 3 | pages = 635–48 | year = 2006 | pmid = 17081983 | doi = 10.1016/j.cell.2006.09.026 | s2cid = 7827573 | doi-access = free }}
* {{cite journal | vauthors = Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D | title = Large-scale mapping of human protein-protein interactions by mass spectrometry | journal = Mol. Syst. Biol. | volume = 3 | issue = 1 | pages = 89 | year = 2007 | pmid = 17353931 | pmc = 1847948 | doi = 10.1038/msb4100134 }}
* {{cite journal | vauthors = Karimi-Busheri F, Rasouli-Nia A, Allalunis-Turner J, Weinfeld M | title = Human polynucleotide kinase participates in repair of DNA double-strand breaks by nonhomologous end joining but not homologous recombination | journal = Cancer Res. | volume = 67 | issue = 14 | pages = 6619–25 | year = 2007 | pmid = 17638872 | doi = 10.1158/0008-5472.CAN-07-0480 | doi-access = free }}
* {{cite journal | vauthors = Mani RS, Fanta M, Karimi-Busheri F, Silver E, Virgen CA, Caldecott KW, Cass CE, Weinfeld M | title = XRCC1 stimulates polynucleotide kinase by enhancing its damage discrimination and displacement from DNA repair intermediates | journal = J. Biol. Chem. | volume = 282 | issue = 38 | pages = 28004–13 | year = 2007 | pmid = 17650498 | doi = 10.1074/jbc.M704867200 | doi-access = free }}
{{refend}}
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