PNKP

PNKP
Identifiers
Aliases	PNKP, EIEE10, MCSZ, PNK, AOA4, polynucleotide kinase 3'-phosphatase, CMT2B2
External IDs	OMIM: 605610; MGI: 1891698; HomoloGene: 5247; GeneCards: PNKP; OMA:PNKP - orthologs
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2BRF, 2W3O
Enzyme activity
Gene location (Human)
Chr.	Chromosome 19 (human)
End	49,878,351 bp
Gene location (Mouse)
Chr.	Chromosome 7 (mouse)
End	44,512,416 bp
RNA expression pattern
	Top expressed in
	right uterine tube; ; granulocyte; ; right adrenal cortex; ; anterior pituitary; ; right lobe of thyroid gland; ; left adrenal gland; ; left adrenal cortex; ; left lobe of thyroid gland; ; right ovary; ; apex of heart;
	Top expressed in
	granulocyte; ; spermatocyte; ; muscle of thigh; ; ventricular zone; ; bone marrow; ; right kidney; ; thymus; ; lip; ; yolk sac; ; superior frontal gyrus;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	transferase activity; nucleotide binding; polydeoxyribonucleotide 5'-hydroxyl-kinase activity; kinase activity; damaged DNA binding; protein binding; catalytic activity; purine nucleotide binding; endonuclease activity; double-stranded DNA binding; hydrolase activity; ATP binding; polynucleotide 3'-phosphatase activity; nucleoside monophosphate kinase activity; polynucleotide kinase activity;
Cellular component	membrane; nucleoplasm; nucleolus; nucleus; mitochondrion;
Biological process	DNA-dependent DNA replication; nucleotide-excision repair, DNA damage removal; positive regulation of telomere capping; phosphorylation; positive regulation of telomere maintenance via telomerase; response to oxidative stress; cellular response to DNA damage stimulus; nucleotide phosphorylation; positive regulation of telomerase activity; response to radiation; metabolism; dephosphorylation; polynucleotide 3' dephosphorylation; DNA repair; nucleic acid phosphodiester bond hydrolysis; negative regulation of protein ADP-ribosylation; nucleoside monophosphate phosphorylation;
	Sources:Amigo / QuickGO
Orthologs
	11284
	59047
	ENSG00000039650
	ENSMUSG00000002963
	Q96T60
	Q9JLV6
	NM_007254
	NM_001290764; NM_001290766; NM_001290767; NM_021549
	NP_009185
	n/a
	Wikidata
View/Edit Human	View/Edit Mouse

Bifunctional polynucleotide phosphatase/kinase is an enzyme that in humans is encoded by the PNKP gene.^[5]^[6]^[7] A detailed structural study of the crystallized mouse protein examined both the 5´-polynucleotide kinase and 3’-polynucleotide phosphatase activities.^[8] 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 interact with DNA polymerase beta^[9] and XRCC1.^[9]^[10]

Role in neurologic disease

The human gene encoding PNKP was observed to be mutated in patients^[11]^[12]^[13]^[14] with microcephaly, seizures and defects in DNA repair. A type of recessive ataxia is also associated with PNKP mutations.^[15] There are also newly characterized pathological variants of PNKP.^[16] Model organisms such as mice and Drosophila have been used to generate further insights.^[17]^[18]

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000039650 – Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000002963 – Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ Jilani A, Ramotar D, Slack C, Ong C, Yang XM, Scherer SW, et al. (September 1999). "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". The Journal of Biological Chemistry. 274 (34): 24176–24186. doi:10.1074/jbc.274.34.24176. PMID 10446192.
↑ Karimi-Busheri F, Daly G, Robins P, Canas B, Pappin DJ, Sgouros J, et al. (September 1999). "Molecular characterization of a human DNA kinase". The Journal of Biological Chemistry. 274 (34): 24187–24194. doi:10.1074/jbc.274.34.24187. PMID 10446193.
↑ "Entrez Gene: PNKP polynucleotide kinase 3'-phosphatase".
↑ Garces F, Pearl LH, Oliver AW (November 2011). "The structural basis for substrate recognition by mammalian polynucleotide kinase 3' phosphatase". Molecular Cell. 44 (3): 385–396. doi:10.1016/j.molcel.2011.08.036. PMC 4820033. PMID 22055185.
1 2 Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, et al. (January 2001). "XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair". Cell. 104 (1): 107–117. doi:10.1016/S0092-8674(01)00195-7. PMID 11163244. S2CID 1487128.
↑ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1) 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
↑ Dumitrache LC, McKinnon PJ (January 2017). "Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease". Mechanisms of Ageing and Development. 161 (Pt A): 121–129. doi:10.1016/j.mad.2016.04.009. PMC 5161711. PMID 27125728.
↑ Shen J, Gilmore EC, Marshall CA, Haddadin M, Reynolds JJ, Eyaid W, et al. (March 2010). "Mutations in PNKP cause microcephaly, seizures and defects in DNA repair". Nature Genetics. 42 (3): 245–249. doi:10.1038/ng.526. PMC 2835984. PMID 20118933.
↑ Issa L, Mueller K, Seufert K, Kraemer N, Rosenkotter H, Ninnemann O, et al. (April 2013). "Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation". Orphanet Journal of Rare Diseases. 8 (1) 59. doi:10.1186/1750-1172-8-59. PMC 3639195. PMID 23587236.
↑ Kalasova I, Hanzlikova H, Gupta N, Li Y, Altmüller J, Reynolds JJ, et al. (April 2019). "Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ". Neurology. Genetics. 5 (2) e320. doi:10.1212/NXG.0000000000000320. PMC 6454307. PMID 31041400.
↑ Bras J, Alonso I, Barbot C, Costa MM, Darwent L, Orme T, et al. (March 2015). "Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4". American Journal of Human Genetics. 96 (3): 474–479. doi:10.1016/j.ajhg.2015.01.005. PMC 4375449. PMID 25728773.
↑ Gatti M, Magri S, Nanetti L, Sarto E, Di Bella D, Salsano E, et al. (November 2019). "From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations". American Journal of Medical Genetics. Part A. 179 (11): 2277–2283. doi:10.1002/ajmg.a.61339. PMID 31436889. S2CID 201275630.
↑ Shimada M, Dumitrache LC, Russell HR, McKinnon PJ (October 2015). "Polynucleotide kinase-phosphatase enables neurogenesis via multiple DNA repair pathways to maintain genome stability". The EMBO Journal. 34 (19): 2465–2480. doi:10.15252/embj.201591363. PMC 4601665. PMID 26290337.
↑ Chakraborty A, Tapryal N, Venkova T, Mitra J, Vasquez V, Sarker AH, et al. (April 2020). "Deficiency in classical nonhomologous end-joining-mediated repair of transcribed genes is linked to SCA3 pathogenesis". Proceedings of the National Academy of Sciences of the United States of America. 117 (14): 8154–8165. Bibcode:2020PNAS..117.8154C. doi:10.1073/pnas.1917280117. PMC 7148577. PMID 32205441.

Chappell C, Hanakahi LA, Karimi-Busheri F, Weinfeld M, West SC (2002). "Involvement of human polynucleotide kinase in double-strand break repair by non-homologous end joining". The EMBO Journal. 21 (11): 2827–2832. doi:10.1093/emboj/21.11.2827. PMC 126026. PMID 12032095.
Mani RS, Karimi-Busheri F, Fanta M, Cass CE, Weinfeld M (2003). "Spectroscopic studies of DNA and ATP binding to human polynucleotide kinase: evidence for a ternary complex". Biochemistry. 42 (41): 12077–12084. doi:10.1021/bi030127b. PMID 14556639.
Loizou JI, El-Khamisy SF, Zlatanou A, Moore DJ, Chan DW, Qin J, et al. (2004). "The protein kinase CK2 facilitates repair of chromosomal DNA single-strand breaks". Cell. 117 (1): 17–28. doi:10.1016/S0092-8674(04)00206-5. PMID 15066279. S2CID 8592154.
Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, et al. (2004). "Functional proteomics mapping of a human signaling pathway". Genome Research. 14 (7): 1324–1332. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
Wiederhold L, Leppard JB, Kedar P, Karimi-Busheri F, Rasouli-Nia A, Weinfeld M, et al. (2004). "AP endonuclease-independent DNA base excision repair in human cells". Molecular Cell. 15 (2): 209–220. doi:10.1016/j.molcel.2004.06.003. PMID 15260972.
Koch CA, Agyei R, Galicia S, Metalnikov P, O'Donnell P, Starostine A, et al. (2004). "Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA ligation by DNA ligase IV". The EMBO Journal. 23 (19): 3874–3885. doi:10.1038/sj.emboj.7600375. PMC 522785. PMID 15385968.
Andersen JS, Lam YW, Leung AK, Ong SE, Lyon CE, Lamond AI, et al. (2005). "Nucleolar proteome dynamics". Nature. 433 (7021): 77–83. Bibcode:2005Natur.433...77A. doi:10.1038/nature03207. PMID 15635413. S2CID 4344740.
Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
Audebert M, Salles B, Weinfeld M, Calsou P (2006). "Involvement of polynucleotide kinase in a poly(ADP-ribose) polymerase-1-dependent DNA double-strand breaks rejoining pathway". Journal of Molecular Biology. 356 (2): 257–265. doi:10.1016/j.jmb.2005.11.028. PMID 16364363.
Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–648. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.
Karimi-Busheri F, Rasouli-Nia A, Allalunis-Turner J, Weinfeld M (2007). "Human polynucleotide kinase participates in repair of DNA double-strand breaks by nonhomologous end joining but not homologous recombination". Cancer Research. 67 (14): 6619–6625. doi:10.1158/0008-5472.CAN-07-0480. PMID 17638872.
Mani RS, Fanta M, Karimi-Busheri F, Silver E, Virgen CA, Caldecott KW, et al. (2007). "XRCC1 stimulates polynucleotide kinase by enhancing its damage discrimination and displacement from DNA repair intermediates". The Journal of Biological Chemistry. 282 (38): 28004–28013. doi:10.1074/jbc.M704867200. PMID 17650498.

This article on a gene on human chromosome 19 is a stub. You can help Wikipedia by adding missing information.

[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000039650 – Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000002963 – 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.

[Jilani_1999-5] Jilani A, Ramotar D, Slack C, Ong C, Yang XM, Scherer SW, et al. (September 1999). "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". The Journal of Biological Chemistry. 274 (34): 24176–24186. doi:10.1074/jbc.274.34.24176. PMID 10446192.

[Karimi-Busheri_1999-6] Karimi-Busheri F, Daly G, Robins P, Canas B, Pappin DJ, Sgouros J, et al. (September 1999). "Molecular characterization of a human DNA kinase". The Journal of Biological Chemistry. 274 (34): 24187–24194. doi:10.1074/jbc.274.34.24187. PMID 10446193.

[entrez-7] "Entrez Gene: PNKP polynucleotide kinase 3'-phosphatase".

[8] Garces F, Pearl LH, Oliver AW (November 2011). "The structural basis for substrate recognition by mammalian polynucleotide kinase 3' phosphatase". Molecular Cell. 44 (3): 385–396. doi:10.1016/j.molcel.2011.08.036. PMC 4820033. PMID 22055185.

[Whitehouse_2001-9] 1 2 Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, Lasko DD, et al. (January 2001). "XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair". Cell. 104 (1): 107–117. doi:10.1016/S0092-8674(01)00195-7. PMID 11163244. S2CID 1487128.

[Ewing_2007-10] Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, et al. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1) 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.

[11] Dumitrache LC, McKinnon PJ (January 2017). "Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease". Mechanisms of Ageing and Development. 161 (Pt A): 121–129. doi:10.1016/j.mad.2016.04.009. PMC 5161711. PMID 27125728.

[12] Shen J, Gilmore EC, Marshall CA, Haddadin M, Reynolds JJ, Eyaid W, et al. (March 2010). "Mutations in PNKP cause microcephaly, seizures and defects in DNA repair". Nature Genetics. 42 (3): 245–249. doi:10.1038/ng.526. PMC 2835984. PMID 20118933.

[13] Issa L, Mueller K, Seufert K, Kraemer N, Rosenkotter H, Ninnemann O, et al. (April 2013). "Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation". Orphanet Journal of Rare Diseases. 8 (1) 59. doi:10.1186/1750-1172-8-59. PMC 3639195. PMID 23587236.

[14] Kalasova I, Hanzlikova H, Gupta N, Li Y, Altmüller J, Reynolds JJ, et al. (April 2019). "Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ". Neurology. Genetics. 5 (2) e320. doi:10.1212/NXG.0000000000000320. PMC 6454307. PMID 31041400.

[15] Bras J, Alonso I, Barbot C, Costa MM, Darwent L, Orme T, et al. (March 2015). "Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4". American Journal of Human Genetics. 96 (3): 474–479. doi:10.1016/j.ajhg.2015.01.005. PMC 4375449. PMID 25728773.

[16] Gatti M, Magri S, Nanetti L, Sarto E, Di Bella D, Salsano E, et al. (November 2019). "From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations". American Journal of Medical Genetics. Part A. 179 (11): 2277–2283. doi:10.1002/ajmg.a.61339. PMID 31436889. S2CID 201275630.

[17] Shimada M, Dumitrache LC, Russell HR, McKinnon PJ (October 2015). "Polynucleotide kinase-phosphatase enables neurogenesis via multiple DNA repair pathways to maintain genome stability". The EMBO Journal. 34 (19): 2465–2480. doi:10.15252/embj.201591363. PMC 4601665. PMID 26290337.

[18] Chakraborty A, Tapryal N, Venkova T, Mitra J, Vasquez V, Sarker AH, et al. (April 2020). "Deficiency in classical nonhomologous end-joining-mediated repair of transcribed genes is linked to SCA3 pathogenesis". Proceedings of the National Academy of Sciences of the United States of America. 117 (14): 8154–8165. Bibcode:2020PNAS..117.8154C. doi:10.1073/pnas.1917280117. PMC 7148577. PMID 32205441.

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PNKP

Interactions

Role in neurologic disease

References

Further reading