{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPolynucleotide kinase 3′‐phosphatase (PNKP) is a dual‐function DNA repair enzyme that restores damaged DNA termini by catalyzing 5′‐phosphorylation and 3′‐dephosphorylation. These activities are essential for re‐establishing the proper 5′-phosphate/3′-hydroxyl ends generated by ionizing radiation, oxidative stress or abortive repair intermediates, and are required for efficient repair through non‐homologous end joining, base excision repair and single-strand break repair. PNKP acts on both nuclear and mitochondrial genomes to safeguard genomic integrity, with its enzymatic functions often regulated by DNA damage–dependent phosphorylation events that promote its activity in distinct repair pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its core catalytic functions, PNKP is intricately regulated through multiple protein–protein interactions and posttranslational modifications that fine-tune its recruitment and activity at damaged DNA sites. It forms dynamic complexes with scaffold proteins such as XRCC1, XRCC4 and DNA ligase IV, and its activity is further modulated by interactions with factors including ataxin-3 and mutant huntingtin that can either stimulate or inhibit its phosphatase function. Moreover, modifications such as phosphorylation, acetylation and SUMOylation—as mediated by enzymes like CBP, p300 and PIAS1—adjust the enzyme’s conformation, stability and subcellular localization. These regulatory mechanisms, supported by structural insights into substrate recognition and assembly into ternary complexes with ATP and oligonucleotides, ensure that PNKP operates in a context-dependent manner to meet the cell’s repair demands."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in the PNKP gene have been linked to a broad spectrum of neurological disorders, underlining the enzyme’s critical role in neuronal genome maintenance. Hypomorphic mutations cause neurodevelopmental conditions such as microcephaly with early-onset seizures (MCSZ), while other variants give rise to degenerative phenotypes including ataxia with oculomotor apraxia, Machado–Joseph disease (spinocerebellar ataxia type 3) and even peripheral neuropathies like Charcot–Marie–Tooth disease. In these clinical settings, defective PNKP—whether due to impaired enzymatic activity, reduced protein stability, mislocalization or compromised recruitment to chromatin—leads to persistent DNA strand breaks, activation of DNA damage responses and subsequent neuronal cell death. Such insights not only enhance our understanding of the pathogenic mechanisms underlying these diverse disorders but also point to potential therapeutic strategies aimed at restoring PNKP function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jun Shen, Edward C Gilmore, Christine A Marshall, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in PNKP cause microcephaly, seizures and defects in DNA repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.526"}], "href": "https://doi.org/10.1038/ng.526"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20118933"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20118933"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Claire Chappell, Les A Hanakahi, Feridoun Karimi-Busheri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of human polynucleotide kinase in double-strand break repair by non-homologous end joining."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/emboj/21.11.2827"}], "href": "https://doi.org/10.1093/emboj/21.11.2827"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12032095"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12032095"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Michael Weinfeld, Rajam S Mani, Ismail Abdou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tidying up loose ends: the role of polynucleotide kinase/phosphatase in DNA strand break repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Trends Biochem Sci (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.tibs.2011.01.006"}], "href": "https://doi.org/10.1016/j.tibs.2011.01.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21353781"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21353781"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Marc Audebert, Bernard Salles, Michael Weinfeld, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of polynucleotide kinase in a poly(ADP-ribose) polymerase-1-dependent DNA double-strand breaks rejoining pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2005.11.028"}], "href": "https://doi.org/10.1016/j.jmb.2005.11.028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16364363"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16364363"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Santi M Mandal, Muralidhar L Hegde, Arpita Chatterjee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of human DNA glycosylase Nei-like 2 (NEIL2) and single strand break repair protein polynucleotide kinase 3'-phosphatase in maintenance of mitochondrial genome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.272179"}], "href": "https://doi.org/10.1074/jbc.M111.272179"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22130663"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22130663"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Feridoun Karimi-Busheri, Aghdass Rasouli-Nia, Joan Allalunis-Turner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human polynucleotide kinase participates in repair of DNA double-strand breaks by nonhomologous end joining but not homologous recombination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-07-0480"}], "href": "https://doi.org/10.1158/0008-5472.CAN-07-0480"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17638872"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17638872"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Angela E Zolner, Ismail Abdou, Ruiqiong Ye, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphorylation of polynucleotide kinase/ phosphatase by DNA-dependent protein kinase and ataxia-telangiectasia mutated regulates its association with sites of DNA damage."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkr647"}], "href": "https://doi.org/10.1093/nar/gkr647"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21824916"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21824916"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "John J Reynolds, Alexandra K Walker, Edward C Gilmore, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gks318"}], "href": "https://doi.org/10.1093/nar/gks318"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22508754"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22508754"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Rajam S Mani, Yaping Yu, Shujuan Fang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dual modes of interaction between XRCC4 and polynucleotide kinase/phosphatase: implications for nonhomologous end joining."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.058719"}], "href": "https://doi.org/10.1074/jbc.M109.058719"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20852255"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20852255"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "R Daniel Aceytuno, Cortt G Piett, Zahra Havali-Shahriari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural and functional characterization of the PNKP-XRCC4-LigIV DNA repair complex."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkx275"}], "href": "https://doi.org/10.1093/nar/gkx275"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28453785"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28453785"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Rui Gao, Anirban Chakraborty, Charlene Geater, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.42988"}], "href": "https://doi.org/10.7554/eLife.42988"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30994454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30994454"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Arpita Chatterjee, Saikat Saha, Anirban Chakraborty, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia type 3 pathogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1004749"}], "href": "https://doi.org/10.1371/journal.pgen.1004749"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25633985"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25633985"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Ammar A E Ali, Rachel M Jukes, Laurence H Pearl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Specific recognition of a multiply phosphorylated motif in the DNA repair scaffold XRCC1 by the FHA domain of human PNK."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkn1086"}], "href": "https://doi.org/10.1093/nar/gkn1086"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19155274"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19155274"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Rajam S Mani, Mesfin Fanta, Feridoun Karimi-Busheri, et al. "}, {"type": "b", "children": [{"type": "t", "text": "XRCC1 stimulates polynucleotide kinase by enhancing its damage discrimination and displacement from DNA repair intermediates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M704867200"}], "href": "https://doi.org/10.1074/jbc.M704867200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17650498"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17650498"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Anirban Chakraborty, Nisha Tapryal, Tatiana Venkova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency in classical nonhomologous end-joining-mediated repair of transcribed genes is linked to SCA3 pathogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1917280117"}], "href": "https://doi.org/10.1073/pnas.1917280117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32205441"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32205441"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Nicolas Coquelle, Zahra Havali-Shahriari, Nina Bernstein, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for the phosphatase activity of polynucleotide kinase/phosphatase on single- and double-stranded DNA substrates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1112036108"}], "href": "https://doi.org/10.1073/pnas.1112036108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22171004"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22171004"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Eva L Morozko, Charlene Smith-Geater, Alejandro Mas Monteys, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2021836118"}], "href": "https://doi.org/10.1073/pnas.2021836118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33468657"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33468657"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Julie Della-Maria, Muralidhar L Hegde, Daniel R McNeill, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The interaction between polynucleotide kinase phosphatase and the DNA repair protein XRCC1 is critical for repair of DNA alkylation damage and stable association at DNA damage sites."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.369975"}], "href": "https://doi.org/10.1074/jbc.M112.369975"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22992732"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22992732"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Claire Breslin, Rajam S Mani, Mesfin Fanta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Rev1 interacting region (RIR) motif in the scaffold protein XRCC1 mediates a low-affinity interaction with polynucleotide kinase/phosphatase (PNKP) during DNA single-strand break repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M117.806638"}], "href": "https://doi.org/10.1074/jbc.M117.806638"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28821613"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28821613"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Nicoline Schiess, David S Zee, Khurram A Siddiqui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel PNKP mutation in siblings with ataxia-oculomotor apraxia type 4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurogenet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/01677063.2017.1322079"}], "href": "https://doi.org/10.1080/01677063.2017.1322079"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28552035"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28552035"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Kaima Tsukada, Mikio Shimada, Rikiya Imamura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The FHA domain of PNKP is essential for its recruitment to DNA damage sites and maintenance of genome stability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mutat Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mrfmmm.2020.111727"}], "href": "https://doi.org/10.1016/j.mrfmmm.2020.111727"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33220551"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33220551"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Azharul Islam, Anirban Chakraborty, Altaf H Sarker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Site-specific acetylation of polynucleotide kinase 3'-phosphatase regulates its distinct role in DNA repair pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkae002"}], "href": "https://doi.org/10.1093/nar/gkae002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38224455"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38224455"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Anirban Chakraborty, Sravan Gopalkrishnashetty Sreenivasmurthy, Wyatt Miller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fructose-2,6-bisphosphate restores DNA repair activity of PNKP and ameliorates neurodegenerative symptoms in Huntington's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2406308121"}], "href": "https://doi.org/10.1073/pnas.2406308121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39298485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39298485"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Rajam S Mani, Inbal Mermershtain, Ismail Abdou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Domain analysis of PNKP-XRCC1 interactions: Influence of genetic variants of XRCC1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA118.004262"}], "href": "https://doi.org/10.1074/jbc.RA118.004262"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30446622"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30446622"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Jose Bras, Isabel Alonso, Clara Barbot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2015.01.005"}], "href": "https://doi.org/10.1016/j.ajhg.2015.01.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25728773"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25728773"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Cathryn Poulton, Renske Oegema, Daphne Heijsman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurogenetics (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10048-012-0351-8"}], "href": "https://doi.org/10.1007/s10048-012-0351-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23224214"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23224214"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Rui Gao, Yongping Liu, Anabela Silva-Fernandes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inactivation of PNKP by mutant ATXN3 triggers apoptosis by activating the DNA damage-response pathway in SCA3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1004834"}], "href": "https://doi.org/10.1371/journal.pgen.1004834"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25590633"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25590633"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Lavinia C Dumitrache, Peter J McKinnon "}, {"type": "b", "children": [{"type": "t", "text": "Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mech Ageing Dev (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mad.2016.04.009"}], "href": "https://doi.org/10.1016/j.mad.2016.04.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27125728"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27125728"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Bingcheng Jiang, J N Mark Glover, Michael Weinfeld "}, {"type": "b", "children": [{"type": "t", "text": "Neurological disorders associated with DNA strand-break processing enzymes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mech Ageing Dev (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mad.2016.07.009"}], "href": "https://doi.org/10.1016/j.mad.2016.07.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27470939"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27470939"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Ilona Kalasova, Richard Hailstone, Janin Bublitz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkaa489"}], "href": "https://doi.org/10.1093/nar/gkaa489"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32504494"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32504494"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Alejandro Leal, Sixto Bogantes-Ledezma, Arif B Ekici, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurogenetics (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10048-018-0555-7"}], "href": "https://doi.org/10.1007/s10048-018-0555-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30039206"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30039206"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Mona Entezam, Masoumeh Razipour, Saeed Talebi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Multi affected pedigree with congenital microcephaly: WES revealed PNKP gene mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain Dev (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.braindev.2018.08.005"}], "href": "https://doi.org/10.1016/j.braindev.2018.08.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30195441"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30195441"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Malgorzata Rychlowska, Abigail Agyapong, Michael Weinfeld, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Zika Virus Induces Mitotic Catastrophe in Human Neural Progenitors by Triggering Unscheduled Mitotic Entry in the Presence of DNA Damage While Functionally Depleting Nuclear PNKP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/jvi.00333-22"}], "href": "https://doi.org/10.1128/jvi.00333-22"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35412344"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35412344"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Azharul Islam, Anirban Chakraborty, Stefano Gambardella, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional analysis of a conserved site mutation in the DNA end processing enzyme PNKP leading to ataxia with oculomotor apraxia type 4 in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbc.2023.104714"}], "href": "https://doi.org/10.1016/j.jbc.2023.104714"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37061005"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37061005"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Pratibha Nair, Abdul Rezzak Hamzeh, Madiha Mohamed, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Microcephalic primordial dwarfism in an Emirati patient with PNKP mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.37766"}], "href": "https://doi.org/10.1002/ajmg.a.37766"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27232581"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27232581"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Luis Bermúdez-Guzmán, Gabriel Jimenez-Huezo, Andrés Arguedas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutational survivorship bias: The case of PNKP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0237682"}], "href": "https://doi.org/10.1371/journal.pone.0237682"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33332469"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33332469"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Mark R Garrelfs, Sanami Takada, Erik-Jan Kamsteeg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Neurol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.pediatrneurol.2020.07.014"}], "href": "https://doi.org/10.1016/j.pediatrneurol.2020.07.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32980744"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32980744"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Gwen Murphy, Leah S Sansbury, Andrew W Bergen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polynucleotide kinase 3' phosphatase variant, dietary variables and risk of adenoma recurrence in the Polyp Prevention Trial."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Cancer Prev (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/CEJ.0b013e3282b6fdb8"}], "href": "https://doi.org/10.1097/CEJ.0b013e3282b6fdb8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18414202"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18414202"}]}]}]}