PNKP_HUMAN
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 03-AUG-2022, entry version 191.
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; 129.
DR CORUM; Q96T60; -.
DR IntAct; Q96T60; 57.
DR MINT; Q96T60; -.
DR STRING; 9606.ENSP00000323511; -.
DR ChEMBL; CHEMBL4523434; -.
DR DEPOD; PNKP; -.
DR GlyGen; Q96T60; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q96T60; -.
DR PhosphoSitePlus; Q96T60; -.
DR BioMuta; PNKP; -.
DR DMDM; 50401132; -.
DR EPD; Q96T60; -.
DR jPOST; Q96T60; -.
DR MassIVE; Q96T60; -.
DR MaxQB; Q96T60; -.
DR PaxDb; Q96T60; -.
DR PeptideAtlas; Q96T60; -.
DR PRIDE; Q96T60; -.
DR ProteomicsDB; 78199; -. [Q96T60-1]
DR Antibodypedia; 1861; 307 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 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; KTREKCV; -.
DR OrthoDB; 1252087at2759; -.
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; 465 hits in 1084 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 182 other tissues.
DR ExpressionAtlas; Q96T60; baseline and differential.
DR Genevisible; Q96T60; HS.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
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: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:0046404; F:polydeoxyribonucleotide 5'-hydroxyl-kinase activity; IDA: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:0046939; P:nucleotide phosphorylation; IDA:UniProtKB.
DR GO; GO:0000718; P:nucleotide-excision repair, DNA damage removal; NAS:UniProtKB.
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 Gene3D; 3.40.50.1000; -; 1.
DR Gene3D; 3.40.50.300; -; 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 Pfam; PF17913; FHA_2; 1.
DR Pfam; PF08645; PNK3P; 1.
DR SUPFAM; SSF49879; SSF49879; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR SUPFAM; SSF56784; SSF56784; 1.
DR TIGRFAMs; TIGR01664; DNA-3'-Pase; 1.
DR TIGRFAMs; TIGR01662; HAD-SF-IIIA; 1.
DR TIGRFAMs; TIGR01663; PNK-3'Pase; 1.
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
