ID PNKP_HUMAN Reviewed; 521 AA. AC Q96T60; Q9BUL2; Q9P1V2; Q9UKU8; Q9UNF8; Q9UNI0; DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 27-MAR-2024, entry version 200. DE RecName: Full=Bifunctional polynucleotide phosphatase/kinase; DE AltName: Full=DNA 5'-kinase/3'-phosphatase; DE AltName: Full=Polynucleotide kinase-3'-phosphatase; DE Includes: DE RecName: Full=Polynucleotide 3'-phosphatase; DE EC=3.1.3.32 {ECO:0000269|PubMed:10446192, ECO:0000269|PubMed:10446193}; DE AltName: Full=2'(3')-polynucleotidase; DE Includes: DE RecName: Full=Polynucleotide 5'-hydroxyl-kinase; DE EC=2.7.1.78; GN Name=PNKP {ECO:0000303|PubMed:10446192, ECO:0000312|HGNC:HGNC:9154}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY, AND RP TISSUE SPECIFICITY. RX PubMed=10446192; DOI=10.1074/jbc.274.34.24176; RA Jilani A., Ramotar D., Slack C., Ong C., Yang X.M., Scherer S.W., RA Lasko D.D.; RT "Molecular cloning of the human gene, PNKP, encoding a polynucleotide RT kinase 3'-phosphatase and evidence for its role in repair of DNA strand RT breaks caused by oxidative damage."; RL J. Biol. Chem. 274:24176-24186(1999). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, FUNCTION, RP CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND RP CHARACTERIZATION. RX PubMed=10446193; DOI=10.1074/jbc.274.34.24187; RA Karimi-Busheri F., Daly G., Robins P., Canas B., Pappin D.J.C., Sgouros J., RA Miller G.G., Fakhrai H., Davis E.M., Le Beau M.M., Weinfeld M.; RT "Molecular characterization of a human DNA kinase."; RL J. Biol. Chem. 274:24187-24194(1999). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Yang H.W., Piao H.Y., Chen Y.Z., Hayashi Y.; RT "Cloning a cDNA which is differently expressed in malignancies."; RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Scorilas A., Katsaros N.; RT "Genomic organization, physical mapping and expression analysis of the RT human polynucleotide kinase-3'-phosphatase (PNKP) gene."; RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-20; VAL-63; SER-180; RP ASN-196 AND GLY-478. RG NIEHS SNPs program; RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Blood, and Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [8] RP FUNCTION, DOMAIN, AND INTERACTION WITH XRCC4. RX PubMed=15385968; DOI=10.1038/sj.emboj.7600375; RA Koch C.A., Agyei R., Galicia S., Metalnikov P., O'Donnell P., RA Starostine A., Weinfeld M., Durocher D.; RT "Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA RT ligation by DNA ligase IV."; RL EMBO J. 23:3874-3885(2004). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-122, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-118 AND THR-122, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-118 AND THR-122, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-118, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [14] RP FUNCTION, DOMAIN, AND INTERACTION WITH XRCC4. RX PubMed=20852255; DOI=10.1074/jbc.m109.058719; RA Mani R.S., Yu Y., Fang S., Lu M., Fanta M., Zolner A.E., Tahbaz N., RA Ramsden D.A., Litchfield D.W., Lees-Miller S.P., Weinfeld M.; RT "Dual modes of interaction between XRCC4 and polynucleotide RT kinase/phosphatase: implications for nonhomologous end joining."; RL J. Biol. Chem. 285:37619-37629(2010). RN [15] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-114 AND THR-118, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [17] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-114; THR-118 AND THR-122, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-118, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [20] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH XRCC4, AND RP CHARACTERIZATION OF VARIANT MCSZ LYS-326. RX PubMed=28453785; DOI=10.1093/nar/gkx275; RA Aceytuno R.D., Piett C.G., Havali-Shahriari Z., Edwards R.A., Rey M., RA Ye R., Javed F., Fang S., Mani R., Weinfeld M., Hammel M., Tainer J.A., RA Schriemer D.C., Lees-Miller S.P., Glover J.N.M.; RT "Structural and functional characterization of the PNKP-XRCC4-LigIV DNA RT repair complex."; RL Nucleic Acids Res. 45:6238-6251(2017). RN [21] RP INVOLVEMENT IN AOA4, AND VARIANTS AOA4 TRP-375 AND THR-408 DEL. RX PubMed=25728773; DOI=10.1016/j.ajhg.2015.01.005; RA Bras J., Alonso I., Barbot C., Costa M.M., Darwent L., Orme T., RA Sequeiros J., Hardy J., Coutinho P., Guerreiro R.; RT "Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4."; RL Am. J. Hum. Genet. 96:474-479(2015). RN [22] RP X-RAY CRYSTALLOGRAPHY (1.4 ANGSTROMS) OF 1-110 ALONE AND IN COMPLEX WITH RP XRCC1 PHOSPHOPEPTIDE, AND DOMAIN FHA. RX PubMed=19155274; DOI=10.1093/nar/gkn1086; RA Ali A.A., Jukes R.M., Pearl L.H., Oliver A.W.; RT "Specific recognition of a multiply phosphorylated motif in the DNA repair RT scaffold XRCC1 by the FHA domain of human PNK."; RL Nucleic Acids Res. 37:1701-1712(2009). RN [23] RP VARIANTS MCSZ PHE-176 AND LYS-326. RX PubMed=20118933; DOI=10.1038/ng.526; RA Shen J., Gilmore E.C., Marshall C.A., Haddadin M., Reynolds J.J., Eyaid W., RA Bodell A., Barry B., Gleason D., Allen K., Ganesh V.S., Chang B.S., RA Grix A., Hill R.S., Topcu M., Caldecott K.W., Barkovich A.J., Walsh C.A.; RT "Mutations in PNKP cause microcephaly, seizures and defects in DNA RT repair."; RL Nat. Genet. 42:245-249(2010). RN [24] RP VARIANT MCSZ PRO-462. RX PubMed=27232581; DOI=10.1002/ajmg.a.37766; RA Nair P., Hamzeh A.R., Mohamed M., Saif F., Tawfiq N., El Halik M., RA Al-Ali M.T., Bastaki F.; RT "Microcephalic primordial dwarfism in an Emirati patient with PNKP RT mutation."; RL Am. J. Med. Genet. A 170:2127-2132(2016). CC -!- FUNCTION: Plays a key role in the repair of DNA damage, functioning as CC part of both the non-homologous end-joining (NHEJ) and base excision CC repair (BER) pathways (PubMed:10446192, PubMed:10446193, CC PubMed:15385968, PubMed:20852255, PubMed:28453785). Through its two CC catalytic activities, PNK ensures that DNA termini are compatible with CC extension and ligation by either removing 3'-phosphates from, or by CC phosphorylating 5'-hydroxyl groups on, the ribose sugar of the DNA CC backbone (PubMed:10446192, PubMed:10446193). CC {ECO:0000269|PubMed:10446192, ECO:0000269|PubMed:10446193, CC ECO:0000269|PubMed:15385968, ECO:0000269|PubMed:20852255, CC ECO:0000269|PubMed:28453785}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a 3'end (2'-deoxyribonucleotide 3'-phosphate)-DNA + H2O = a CC 3'-end 2'-deoxyribonucleotide-DNA + phosphate; Xref=Rhea:RHEA:14113, CC Rhea:RHEA-COMP:13863, Rhea:RHEA-COMP:13864, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:138147, ChEBI:CHEBI:138148; CC EC=3.1.3.32; Evidence={ECO:0000269|PubMed:10446192, CC ECO:0000269|PubMed:10446193}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 5'-end dephospho-2'-deoxyribonucleoside-DNA + ATP = a 5'-end CC 5'-monophospho-2'-deoxyribonucleoside-DNA + ADP + H(+); CC Xref=Rhea:RHEA:15669, Rhea:RHEA-COMP:13180, Rhea:RHEA-COMP:13184, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:136412, CC ChEBI:CHEBI:136416, ChEBI:CHEBI:456216; EC=2.7.1.78; CC Evidence={ECO:0000269|PubMed:10446192, ECO:0000269|PubMed:10446193}; CC -!- SUBUNIT: Monomer (By similarity). Interacts (via FHA domain) with CC XRCC4; mainly interacts with XRCC4 phosphorylated by CK2 but is also CC able to interact at much lower level with unphosphorylated PNKP CC (PubMed:15385968, PubMed:20852255, PubMed:28453785). CC {ECO:0000250|UniProtKB:Q9JLV6, ECO:0000269|PubMed:15385968, CC ECO:0000269|PubMed:20852255, ECO:0000269|PubMed:28453785}. CC -!- INTERACTION: CC Q96T60; Q9UGQ2: CACFD1; NbExp=3; IntAct=EBI-1045072, EBI-8652492; CC Q96T60; Q13554-3: CAMK2B; NbExp=3; IntAct=EBI-1045072, EBI-11523526; CC Q96T60; Q9BWT7: CARD10; NbExp=3; IntAct=EBI-1045072, EBI-3866279; CC Q96T60; Q49A88-3: CCDC14; NbExp=3; IntAct=EBI-1045072, EBI-12105646; CC Q96T60; Q86WV7: CCDC43; NbExp=3; IntAct=EBI-1045072, EBI-10260148; CC Q96T60; P28329-3: CHAT; NbExp=3; IntAct=EBI-1045072, EBI-25837549; CC Q96T60; Q8N5K1: CISD2; NbExp=3; IntAct=EBI-1045072, EBI-1045797; CC Q96T60; Q8N137: CNTROB; NbExp=3; IntAct=EBI-1045072, EBI-947360; CC Q96T60; Q9UMD9: COL17A1; NbExp=3; IntAct=EBI-1045072, EBI-2528742; CC Q96T60; Q92997: DVL3; NbExp=3; IntAct=EBI-1045072, EBI-739789; CC Q96T60; Q8N9I5: FADS6; NbExp=3; IntAct=EBI-1045072, EBI-3943864; CC Q96T60; P22607: FGFR3; NbExp=3; IntAct=EBI-1045072, EBI-348399; CC Q96T60; O43524: FOXO3; NbExp=2; IntAct=EBI-1045072, EBI-1644164; CC Q96T60; O95995: GAS8; NbExp=3; IntAct=EBI-1045072, EBI-1052570; CC Q96T60; Q13422: IKZF1; NbExp=3; IntAct=EBI-1045072, EBI-745305; CC Q96T60; Q13422-7: IKZF1; NbExp=3; IntAct=EBI-1045072, EBI-11522367; CC Q96T60; Q63ZY3: KANK2; NbExp=3; IntAct=EBI-1045072, EBI-2556193; CC Q96T60; Q53G59: KLHL12; NbExp=3; IntAct=EBI-1045072, EBI-740929; CC Q96T60; P23508: MCC; NbExp=3; IntAct=EBI-1045072, EBI-307531; CC Q96T60; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-1045072, EBI-16439278; CC Q96T60; Q99735: MGST2; NbExp=3; IntAct=EBI-1045072, EBI-11324706; CC Q96T60; Q8NCY6: MSANTD4; NbExp=3; IntAct=EBI-1045072, EBI-7850168; CC Q96T60; Q9NRD5: PICK1; NbExp=3; IntAct=EBI-1045072, EBI-79165; CC Q96T60; Q96PV4: PNMA5; NbExp=3; IntAct=EBI-1045072, EBI-10171633; CC Q96T60; O43586: PSTPIP1; NbExp=3; IntAct=EBI-1045072, EBI-1050964; CC Q96T60; Q9NS64: RPRM; NbExp=3; IntAct=EBI-1045072, EBI-1052363; CC Q96T60; Q8WV19: SFT2D1; NbExp=3; IntAct=EBI-1045072, EBI-2854842; CC Q96T60; O60749: SNX2; NbExp=3; IntAct=EBI-1045072, EBI-1046690; CC Q96T60; Q02446: SP4; NbExp=3; IntAct=EBI-1045072, EBI-10198587; CC Q96T60; O43759-2: SYNGR1; NbExp=3; IntAct=EBI-1045072, EBI-12187159; CC Q96T60; O43761: SYNGR3; NbExp=3; IntAct=EBI-1045072, EBI-11321949; CC Q96T60; P08247: SYP; NbExp=3; IntAct=EBI-1045072, EBI-9071725; CC Q96T60; Q15633: TARBP2; NbExp=3; IntAct=EBI-1045072, EBI-978581; CC Q96T60; Q86TI0: TBC1D1; NbExp=3; IntAct=EBI-1045072, EBI-1644036; CC Q96T60; Q9NVV9: THAP1; NbExp=3; IntAct=EBI-1045072, EBI-741515; CC Q96T60; Q8WW34-2: TMEM239; NbExp=3; IntAct=EBI-1045072, EBI-11528917; CC Q96T60; Q15025: TNIP1; NbExp=6; IntAct=EBI-1045072, EBI-357849; CC Q96T60; O94972: TRIM37; NbExp=4; IntAct=EBI-1045072, EBI-741602; CC Q96T60; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-1045072, EBI-741480; CC Q96T60; P18887: XRCC1; NbExp=6; IntAct=EBI-1045072, EBI-947466; CC Q96T60; Q13426: XRCC4; NbExp=9; IntAct=EBI-1045072, EBI-717592; CC Q96T60; O43829: ZBTB14; NbExp=6; IntAct=EBI-1045072, EBI-10176632; CC Q96T60; Q9UID6: ZNF639; NbExp=6; IntAct=EBI-1045072, EBI-947476; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:10446193}. Chromosome CC {ECO:0000269|PubMed:28453785}. Note=Localizes to site of double-strand CC breaks. {ECO:0000269|PubMed:28453785}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q96T60-1; Sequence=Displayed; CC Name=2; CC IsoId=Q96T60-2; Sequence=VSP_055500; CC -!- TISSUE SPECIFICITY: Expressed in many tissues with highest expression CC in spleen and testis, and lowest expression in small intestine CC (PubMed:10446192). Expressed in higher amount in pancreas, heart and CC kidney and at lower levels in brain, lung and liver (PubMed:10446193). CC {ECO:0000269|PubMed:10446192, ECO:0000269|PubMed:10446193}. CC -!- DOMAIN: The FHA domain binds threonine-phosphorylated peptides from CC XRCC1/4, and is responsible for the recruitment of PNKP to the sites of CC DNA repair. The affinity is ten times greater if peptides are also CC phosphorylated on the serine preceeding the phosphothreonine. CC {ECO:0000269|PubMed:15385968, ECO:0000269|PubMed:19155274, CC ECO:0000269|PubMed:20852255}. CC -!- DISEASE: Microcephaly, seizures, and developmental delay (MCSZ) CC [MIM:613402]: An autosomal recessive neurodevelopmental disorder CC characterized by infantile-onset seizures, microcephaly, severe CC intellectual disability and delayed motor milestones with absent speech CC or only achieving a few words. Most patients also have behavioral CC problems with hyperactivity. Microcephaly is progressive and without CC neuronal migration or structural abnormalities, consistent with primary CC microcephaly. {ECO:0000269|PubMed:20118933, CC ECO:0000269|PubMed:27232581, ECO:0000269|PubMed:28453785}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Ataxia-oculomotor apraxia 4 (AOA4) [MIM:616267]: An autosomal CC recessive disease characterized by cerebellar ataxia, oculomotor CC apraxia, areflexia and peripheral neuropathy. CC {ECO:0000269|PubMed:25728773}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: In the N-terminal section; belongs to the DNA 3' CC phosphatase family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAD47379.1; Type=Frameshift; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/pnkp/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF126486; AAD51135.1; -; mRNA. DR EMBL; AF125807; AAD50639.1; -; mRNA. DR EMBL; AF120499; AAD47379.1; ALT_FRAME; mRNA. DR EMBL; AF354258; AAK57340.1; -; Genomic_DNA. DR EMBL; AY133033; AAM82170.1; -; Genomic_DNA. DR EMBL; AC018766; AAF44716.1; -; Genomic_DNA. DR EMBL; BC002519; AAH02519.2; -; mRNA. DR EMBL; BC033822; AAH33822.1; -; mRNA. DR CCDS; CCDS12783.1; -. [Q96T60-1] DR RefSeq; NP_009185.2; NM_007254.3. [Q96T60-1] DR PDB; 2BRF; X-ray; 1.40 A; A=1-110. DR PDB; 2W3O; X-ray; 1.85 A; A/B=1-110. DR PDBsum; 2BRF; -. DR PDBsum; 2W3O; -. DR AlphaFoldDB; Q96T60; -. DR SMR; Q96T60; -. DR BioGRID; 116440; 138. DR ComplexPortal; CPX-793; XRCC1 DNA repair complex. DR CORUM; Q96T60; -. DR IntAct; Q96T60; 58. DR MINT; Q96T60; -. DR STRING; 9606.ENSP00000323511; -. DR BindingDB; Q96T60; -. DR ChEMBL; CHEMBL4523434; -. DR DEPOD; PNKP; -. DR GlyGen; Q96T60; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; Q96T60; -. DR PhosphoSitePlus; Q96T60; -. DR SwissPalm; Q96T60; -. DR BioMuta; PNKP; -. DR DMDM; 50401132; -. DR EPD; Q96T60; -. DR jPOST; Q96T60; -. DR MassIVE; Q96T60; -. DR MaxQB; Q96T60; -. DR PaxDb; 9606-ENSP00000323511; -. DR PeptideAtlas; Q96T60; -. DR ProteomicsDB; 78199; -. [Q96T60-1] DR Pumba; Q96T60; -. DR Antibodypedia; 1861; 346 antibodies from 36 providers. DR DNASU; 11284; -. DR Ensembl; ENST00000322344.8; ENSP00000323511.2; ENSG00000039650.12. [Q96T60-1] DR Ensembl; ENST00000596014.5; ENSP00000472300.1; ENSG00000039650.12. [Q96T60-1] DR GeneID; 11284; -. DR KEGG; hsa:11284; -. DR MANE-Select; ENST00000322344.8; ENSP00000323511.2; NM_007254.4; NP_009185.2. DR UCSC; uc002pqj.4; human. [Q96T60-1] DR AGR; HGNC:9154; -. DR CTD; 11284; -. DR DisGeNET; 11284; -. DR GeneCards; PNKP; -. DR HGNC; HGNC:9154; PNKP. DR HPA; ENSG00000039650; Low tissue specificity. DR MalaCards; PNKP; -. DR MIM; 605610; gene. DR MIM; 613402; phenotype. DR MIM; 616267; phenotype. DR neXtProt; NX_Q96T60; -. DR OpenTargets; ENSG00000039650; -. DR Orphanet; 459033; Ataxia-oculomotor apraxia type 4. DR Orphanet; 101101; Charcot-Marie-Tooth disease type 2B2. DR Orphanet; 1934; Early infantile epileptic encephalopathy. DR PharmGKB; PA33477; -. DR VEuPathDB; HostDB:ENSG00000039650; -. DR eggNOG; KOG2134; Eukaryota. DR GeneTree; ENSGT00940000159302; -. DR HOGENOM; CLU_014938_1_1_1; -. DR InParanoid; Q96T60; -. DR OMA; AADWKWW; -. DR OrthoDB; 5490169at2759; -. DR PhylomeDB; Q96T60; -. DR TreeFam; TF313738; -. DR BRENDA; 2.7.1.78; 2681. DR BRENDA; 3.1.3.32; 2681. DR PathwayCommons; Q96T60; -. DR Reactome; R-HSA-5649702; APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway. DR SignaLink; Q96T60; -. DR SIGNOR; Q96T60; -. DR BioGRID-ORCS; 11284; 494 hits in 1175 CRISPR screens. DR EvolutionaryTrace; Q96T60; -. DR GeneWiki; PNKP; -. DR GenomeRNAi; 11284; -. DR Pharos; Q96T60; Tchem. DR PRO; PR:Q96T60; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q96T60; Protein. DR Bgee; ENSG00000039650; Expressed in right uterine tube and 184 other cell types or tissues. DR ExpressionAtlas; Q96T60; baseline and differential. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0005730; C:nucleolus; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB. DR GO; GO:0046404; F:ATP-dependent polydeoxyribonucleotide 5'-hydroxyl-kinase activity; IDA:UniProtKB. DR GO; GO:0003684; F:damaged DNA binding; NAS:UniProtKB. DR GO; GO:0003690; F:double-stranded DNA binding; IBA:GO_Central. DR GO; GO:0004519; F:endonuclease activity; NAS:UniProtKB. DR GO; GO:0046403; F:polynucleotide 3'-phosphatase activity; IDA:UniProtKB. DR GO; GO:0017076; F:purine nucleotide binding; NAS:UniProtKB. DR GO; GO:0006287; P:base-excision repair, gap-filling; TAS:Reactome. DR GO; GO:0051103; P:DNA ligation involved in DNA repair; IDA:UniProtKB. DR GO; GO:0006281; P:DNA repair; IGI:UniProtKB. DR GO; GO:0006261; P:DNA-templated DNA replication; NAS:UniProtKB. DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; IDA:UniProtKB. DR GO; GO:0010836; P:negative regulation of protein ADP-ribosylation; IMP:UniProtKB. DR GO; GO:0006289; P:nucleotide-excision repair; TAS:UniProtKB. DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:2001034; P:positive regulation of double-strand break repair via nonhomologous end joining; IMP:CACAO. DR GO; GO:0051973; P:positive regulation of telomerase activity; IMP:BHF-UCL. DR GO; GO:1904355; P:positive regulation of telomere capping; IMP:BHF-UCL. DR GO; GO:0032212; P:positive regulation of telomere maintenance via telomerase; IMP:BHF-UCL. DR GO; GO:0006979; P:response to oxidative stress; IDA:UniProtKB. DR GO; GO:0009314; P:response to radiation; TAS:UniProtKB. DR CDD; cd22736; FHA_PNKP; 1. DR CDD; cd01625; HAD_PNP; 1. DR Gene3D; 2.60.200.20; -; 1. DR Gene3D; 3.40.50.1000; HAD superfamily/HAD-like; 1. DR Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1. DR InterPro; IPR041388; FHA_2. DR InterPro; IPR036412; HAD-like_sf. DR InterPro; IPR006549; HAD-SF_hydro_IIIA. DR InterPro; IPR023214; HAD_sf. DR InterPro; IPR027417; P-loop_NTPase. DR InterPro; IPR013954; PNK3P. DR InterPro; IPR006550; PNKP. DR InterPro; IPR006551; Polynucleotide_phosphatase. DR InterPro; IPR008984; SMAD_FHA_dom_sf. DR NCBIfam; TIGR01664; DNA-3'-Pase; 1. DR NCBIfam; TIGR01662; HAD-SF-IIIA; 1. DR NCBIfam; TIGR01663; PNK-3'Pase; 1. DR PANTHER; PTHR12083; BIFUNCTIONAL POLYNUCLEOTIDE PHOSPHATASE/KINASE; 1. DR PANTHER; PTHR12083:SF9; BIFUNCTIONAL POLYNUCLEOTIDE PHOSPHATASE_KINASE; 1. DR Pfam; PF13671; AAA_33; 1. DR Pfam; PF17913; FHA_2; 1. DR Pfam; PF08645; PNK3P; 1. DR SUPFAM; SSF56784; HAD-like; 1. DR SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1. DR SUPFAM; SSF49879; SMAD/FHA domain; 1. DR Genevisible; Q96T60; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; ATP-binding; Chromosome; KW Direct protein sequencing; Disease variant; DNA damage; DNA repair; KW Epilepsy; Hydrolase; Intellectual disability; Kinase; KW Multifunctional enzyme; Neurodegeneration; Nucleotide-binding; Nucleus; KW Phosphoprotein; Primary microcephaly; Reference proteome; Transferase. FT CHAIN 1..521 FT /note="Bifunctional polynucleotide phosphatase/kinase" FT /id="PRO_0000058478" FT DOMAIN 6..110 FT /note="FHA" FT REGION 109..143 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 146..337 FT /note="Phosphatase" FT /evidence="ECO:0000250|UniProtKB:Q9JLV6" FT REGION 341..516 FT /note="Kinase" FT /evidence="ECO:0000250|UniProtKB:Q9JLV6" FT COMPBIAS 127..143 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 372..379 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:22814378" FT MOD_RES 114 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 118 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 122 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:23186163" FT VAR_SEQ 1..50 FT /note="MGEVEAPGRLWLESPPGGAPPIFLPSDGQALVLGRGPLTQVTDRKCSRTQ FT -> MQILTPPLQSS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_055500" FT VARIANT 20 FT /note="P -> S (in dbSNP:rs3739168)" FT /evidence="ECO:0000269|Ref.5" FT /id="VAR_019260" FT VARIANT 63 FT /note="A -> V (in dbSNP:rs3739173)" FT /evidence="ECO:0000269|Ref.5" FT /id="VAR_019261" FT VARIANT 176 FT /note="L -> F (in MCSZ; dbSNP:rs267606957)" FT /evidence="ECO:0000269|PubMed:20118933" FT /id="VAR_063835" FT VARIANT 180 FT /note="R -> S (in dbSNP:rs3739185)" FT /evidence="ECO:0000269|Ref.5" FT /id="VAR_019262" FT VARIANT 196 FT /note="Y -> N (in dbSNP:rs3739186)" FT /evidence="ECO:0000269|Ref.5" FT /id="VAR_019263" FT VARIANT 326 FT /note="E -> K (in MCSZ; impaired recruitment to DNA damage FT sites; dbSNP:rs267606956)" FT /evidence="ECO:0000269|PubMed:20118933, FT ECO:0000269|PubMed:28453785" FT /id="VAR_063836" FT VARIANT 375 FT /note="G -> W (in AOA4; dbSNP:rs786203983)" FT /evidence="ECO:0000269|PubMed:25728773" FT /id="VAR_073369" FT VARIANT 408 FT /note="Missing (in AOA4)" FT /evidence="ECO:0000269|PubMed:25728773" FT /id="VAR_073370" FT VARIANT 462 FT /note="R -> P (in MCSZ; atypical phenotype; FT dbSNP:rs376854895)" FT /evidence="ECO:0000269|PubMed:27232581" FT /id="VAR_076537" FT VARIANT 478 FT /note="V -> G (in dbSNP:rs3739206)" FT /evidence="ECO:0000269|Ref.5" FT /id="VAR_019264" FT CONFLICT 6 FT /note="A -> P (in Ref. 2; AAD50639)" FT /evidence="ECO:0000305" FT CONFLICT 18 FT /note="G -> E (in Ref. 1; AAD51135)" FT /evidence="ECO:0000305" FT CONFLICT 458 FT /note="R -> C (in Ref. 3; AAD47379)" FT /evidence="ECO:0000305" FT STRAND 9..13 FT /evidence="ECO:0007829|PDB:2BRF" FT STRAND 31..33 FT /evidence="ECO:0007829|PDB:2BRF" FT TURN 37..40 FT /evidence="ECO:0007829|PDB:2BRF" FT STRAND 51..56 FT /evidence="ECO:0007829|PDB:2BRF" FT TURN 57..60 FT /evidence="ECO:0007829|PDB:2BRF" FT STRAND 61..66 FT /evidence="ECO:0007829|PDB:2BRF" FT STRAND 68..70 FT /evidence="ECO:0007829|PDB:2BRF" FT STRAND 84..88 FT /evidence="ECO:0007829|PDB:2BRF" FT STRAND 92..96 FT /evidence="ECO:0007829|PDB:2BRF" FT STRAND 99..107 FT /evidence="ECO:0007829|PDB:2BRF" SQ SEQUENCE 521 AA; 57076 MW; 22B5C94D41E62516 CRC64; MGEVEAPGRL WLESPPGGAP PIFLPSDGQA LVLGRGPLTQ VTDRKCSRTQ VELVADPETR TVAVKQLGVN PSTTGTQELK PGLEGSLGVG DTLYLVNGLH PLTLRWEETR TPESQPDTPP GTPLVSQDEK RDAELPKKRM RKSNPGWENL EKLLVFTAAG VKPQGKVAGF DLDGTLITTR SGKVFPTGPS DWRILYPEIP RKLRELEAEG YKLVIFTNQM SIGRGKLPAE EFKAKVEAVV EKLGVPFQVL VATHAGLYRK PVTGMWDHLQ EQANDGTPIS IGDSIFVGDA AGRPANWAPG RKKKDFSCAD RLFALNLGLP FATPEEFFLK WPAAGFELPA FDPRTVSRSG PLCLPESRAL LSASPEVVVA VGFPGAGKST FLKKHLVSAG YVHVNRDTLG SWQRCVTTCE TALKQGKRVA IDNTNPDAAS RARYVQCARA AGVPCRCFLF TATLEQARHN NRFREMTDSS HIPVSDMVMY GYRKQFEAPT LAEGFSAILE IPFRLWVEPR LGRLYCQFSE G //