Biology:PNKP

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Bifunctional polynucleotide phosphatase/kinase is an enzyme that in humans is encoded by the PNKP gene.[1][2][3] A detailed structural study of the crystallized mouse protein examined both the 5´-polynucleotide kinase and 3’-polynucleotide phosphatase activities.[4] 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[5] and XRCC1.[5][6]

Role in neurologic disease

The human gene encoding PNKP was observed to be mutated in patients[7][8][9][10] with microcephaly, seizures and defects in DNA repair. A type of recessive ataxia is also associated with PNKP mutations.[11] There are also newly characterized pathological variants of PNKP.[12] Model organisms such as mice and Drosophila have been used to generate further insights.[13][14]

References

  1. "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". J. Biol. Chem. 274 (34): 24176–86. September 1999. doi:10.1074/jbc.274.34.24176. PMID 10446192. 
  2. "Molecular characterization of a human DNA kinase". J. Biol. Chem. 274 (34): 24187–94. September 1999. doi:10.1074/jbc.274.34.24187. PMID 10446193. 
  3. "Entrez Gene: PNKP polynucleotide kinase 3'-phosphatase". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=11284. 
  4. Garces, Fernando; Pearl, Laurence H.; Oliver, Antony W. (November 2011). "The Structural Basis for Substrate Recognition by Mammalian Polynucleotide Kinase 3′ Phosphatase" (in en). Molecular Cell 44 (3): 385–396. doi:10.1016/j.molcel.2011.08.036. PMID 22055185. 
  5. 5.0 5.1 "XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair". Cell 104 (1): 107–17. January 2001. doi:10.1016/S0092-8674(01)00195-7. PMID 11163244. 
  6. "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3 (1): 89. 2007. doi:10.1038/msb4100134. PMID 17353931. 
  7. Dumitrache, Lavinia C.; McKinnon, Peter J. (2017). "Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease" (in en). Mechanisms of Ageing and Development 161 (Pt A): 121–129. doi:10.1016/j.mad.2016.04.009. PMID 27125728. 
  8. Shen, Jun; Gilmore, Edward C; Marshall, Christine A; Haddadin, Mary; Reynolds, John J; Eyaid, Wafaa; Bodell, Adria; Barry, Brenda et al. (2010). "Mutations in PNKP cause microcephaly, seizures and defects in DNA repair" (in en). Nat Genet 42 (3): 245–249. doi:10.1038/ng.526. ISSN 1061-4036. PMID 20118933. 
  9. Issa, Lina; Mueller, Katrin; Seufert, Katja; Kraemer, Nadine; Rosenkotter, Henning; Ninnemann, Olaf; Buob, Michael; Kaindl, Angela M et al. (2013). "Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation" (in en). Orphanet Journal of Rare Diseases 8 (1): 59. doi:10.1186/1750-1172-8-59. ISSN 1750-1172. PMID 23587236. 
  10. Kalasova, Ilona; Hanzlikova, Hana; Gupta, Neerja; Li, Yun; Altmüller, Janine; Reynolds, John J.; Stewart, Grant S.; Wollnik, Bernd et al. (2019). "Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ" (in en). Neurol Genet 5 (2): e320. doi:10.1212/NXG.0000000000000320. ISSN 2376-7839. PMID 31041400. 
  11. Bras, Jose; Alonso, Isabel; Barbot, Clara; Costa, Maria Manuela; Darwent, Lee; Orme, Tatiana; Sequeiros, Jorge; Hardy, John et al. (2015). "Mutations in PNKP Cause Recessive Ataxia with Oculomotor Apraxia Type 4" (in en). The American Journal of Human Genetics 96 (3): 474–479. doi:10.1016/j.ajhg.2015.01.005. PMID 25728773. 
  12. Gatti, Marta; Magri, Stefania; Nanetti, Lorenzo; Sarto, Elisa; Di Bella, Daniela; Salsano, Ettore; Pantaleoni, Chiara; Mariotti, Caterina et al. (2019). "From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations" (in en). American Journal of Medical Genetics Part A 179 (11): 2277–2283. doi:10.1002/ajmg.a.61339. ISSN 1552-4825. PMID 31436889. 
  13. Shimada, Mikio; Dumitrache, Lavinia C; Russell, Helen R; McKinnon, Peter J (2015). "Polynucleotide kinase–phosphatase enables neurogenesis via multiple DNA repair pathways to maintain genome stability" (in en). The EMBO Journal 34 (19): 2465–2480. doi:10.15252/embj.201591363. ISSN 0261-4189. PMID 26290337. 
  14. Chakraborty, Anirban; Tapryal, Nisha; Venkova, Tatiana; Mitra, Joy; Vasquez, Velmarini; Sarker, Altaf H.; Duarte-Silva, Sara; Huai, Weihan et al. (2020-04-07). "Deficiency in classical nonhomologous end-joining–mediated repair of transcribed genes is linked to SCA3 pathogenesis" (in en). Proceedings of the National Academy of Sciences 117 (14): 8154–8165. doi:10.1073/pnas.1917280117. ISSN 0027-8424. PMID 32205441. Bibcode2020PNAS..117.8154C. 

Further reading