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Protein

Poly [ADP-ribose] polymerase 9

Gene

PARP9

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

ADP-ribosyltransferase which, in association with E3 ligase DTX3L, plays a role in DNA damage repair and in immune responses including interferon-mediated antiviral defenses (PubMed:16809771, PubMed:23230272, PubMed:26479788, PubMed:27796300). Within the complex, enhances DTX3L E3 ligase activity which is further enhanced by PARP9 binding to poly(ADP-ribose) (PubMed:28525742). In association with DTX3L and in presence of E1 and E2 enzymes, mediates NAD+-dependent mono-ADP-ribosylation of ubiquitin which prevents ubiquitin conjugation to substrates such as histones (PubMed:28525742). During DNA repair, PARP1 recruits PARP9/BAL1-DTX3L complex to DNA damage sites via PARP9 binding to ribosylated PARP1 (PubMed:23230272). Subsequent PARP1-dependent PARP9/BAL1-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272, PubMed:28525742). In response to DNA damage, PARP9-DTX3L complex is required for efficient non-homologous end joining (NHEJ); the complex function is negatively modulated by PARP9 activity (PubMed:28525742). Dispensable for B-cell receptor (BCR) assembly through V(D)J recombination and class switch recombination (CSR) (By similarity). In macrophages, positively regulates pro-inflammatory cytokines production in response to IFNG stimulation by suppressing PARP14-mediated STAT1 ADP-ribosylation and thus promoting STAT1 phosphorylation (PubMed:27796300). Also suppresses PARP14-mediated STAT6 ADP-ribosylation (PubMed:27796300).By similarity5 Publications

Catalytic activityi

NAD+ + (ADP-D-ribosyl)(n)-acceptor = nicotinamide + (ADP-D-ribosyl)(n+1)-acceptor.PROSITE-ProRule annotation1 Publication

Enzyme regulationi

Binding to poly(ADP-ribose) does not affect its activity.1 Publication

Kineticsi

  1. KM=196 µM for NAD+1 Publication

    GO - Molecular functioni

    • ADP-D-ribose binding Source: UniProtKB
    • enzyme binding Source: UniProtKB
    • enzyme inhibitor activity Source: UniProtKB
    • histone binding Source: UniProtKB
    • NAD+ ADP-ribosyltransferase activity Source: UniProtKB
    • STAT family protein binding Source: UniProtKB
    • transcriptional repressor activity, RNA polymerase II transcription factor binding Source: UniProtKB
    • ubiquitin-like protein ligase binding Source: UniProtKB

    GO - Biological processi

    • cell migration Source: UniProtKB
    • double-strand break repair Source: UniProtKB
    • NAD biosynthesis via nicotinamide riboside salvage pathway Source: Reactome
    • negative regulation of catalytic activity Source: UniProtKB
    • negative regulation of gene expression Source: UniProtKB
    • negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    • positive regulation of chromatin binding Source: UniProtKB
    • positive regulation of defense response to virus by host Source: UniProtKB
    • positive regulation of double-strand break repair via nonhomologous end joining Source: UniProtKB
    • positive regulation of interferon-gamma-mediated signaling pathway Source: UniProtKB
    • positive regulation of protein localization to nucleus Source: UniProtKB
    • positive regulation of transcription, DNA-templated Source: UniProtKB
    • positive regulation of tyrosine phosphorylation of STAT protein Source: UniProtKB
    • posttranscriptional regulation of gene expression Source: UniProtKB
    • protein ADP-ribosylation Source: UniProtKB
    • regulation of response to interferon-gamma Source: UniProtKB

    Keywordsi

    Molecular functionTransferase
    Biological processAntiviral defense, DNA damage, DNA repair, Immunity, Innate immunity
    LigandNAD

    Enzyme and pathway databases

    ReactomeiR-HSA-197264. Nicotinamide salvaging.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Poly [ADP-ribose] polymerase 9 (EC:2.4.2.30PROSITE-ProRule annotation1 Publication)
    Short name:
    PARP-9
    Alternative name(s):
    ADP-ribosyltransferase diphtheria toxin-like 9
    Short name:
    ARTD9
    B aggressive lymphoma protein
    Gene namesi
    Name:PARP9
    Synonyms:BAL, BAL1
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 3

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000138496.16.
    HGNCiHGNC:24118. PARP9.

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

    Overexpressed at significantly higher levels in fatal high-risk diffuse large B-cell lymphomas (DLB-CL) compared to cured low-risk tumors. Overexpression in B-cell lymphoma transfectants may promote malignant B-cell migration. May therefore be involved in promoting B-cell migration and dissemination of high-risk DLB-CL tumors (PubMed:11110709).1 Publication

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi147G → E: Reduces the binding to poly(ADP-ribose) by 50 percent and prevents increase in DTX3L-mediated histone ubiquitination without affecting ubiquitin ADP ribosylation, interaction with DTX3L and STAT1 and DTX3L catalytic activity; when associated with E-346. 2 Publications1
    Mutagenesisi346G → E: Reduces the binding to poly(ADP-ribose) by 50 percent and prevents increase in DTX3L-mediated histone ubiquitination without affecting ubiquitin ADP ribosylation, interaction with DTX3L and STAT1 and DTX3L catalytic activity; when associated with E-147. 2 Publications1
    Mutagenesisi719 – 722Missing : Loss of ADP ribosylation activity and interaction with DTX3L. 1 Publication4
    Mutagenesisi737Y → A: No defect in ubiquitin ADP ribosylation and the interaction with DTX3L. 1 Publication1
    Mutagenesisi738F → K: Severe reduction in ubiquitin ADP ribosylation. No effect on the interaction with DTX3L and on DTX3L E3 ligase activity. Increases DNA repair. 1 Publication1
    Mutagenesisi766 – 769Missing : Loss of ADP ribosylation activity and interaction with DTX3L. 1 Publication4
    Mutagenesisi780 – 784Missing : Reduces ADP ribosylation activity and interaction with DTX3L. 1 Publication5
    Mutagenesisi802 – 803PE → AA: No defect in ADP ribosylation and interaction with DTX3L. 1 Publication2
    Mutagenesisi831 – 854Missing : No defect in ADP ribosylation and interaction with DTX3L. 1 PublicationAdd BLAST24

    Organism-specific databases

    DisGeNETi83666.
    OpenTargetsiENSG00000138496.
    PharmGKBiPA134870403.

    Polymorphism and mutation databases

    BioMutaiPARP9.
    DMDMi48474734.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00002113391 – 854Poly [ADP-ribose] polymerase 9Add BLAST854

    Post-translational modificationi

    ADP-ribosylated by PARP14.1 Publication

    Keywords - PTMi

    ADP-ribosylation

    Proteomic databases

    EPDiQ8IXQ6.
    MaxQBiQ8IXQ6.
    PaxDbiQ8IXQ6.
    PeptideAtlasiQ8IXQ6.
    PRIDEiQ8IXQ6.

    PTM databases

    iPTMnetiQ8IXQ6.
    PhosphoSitePlusiQ8IXQ6.

    Expressioni

    Tissue specificityi

    Expressed in lymphocyte-rich tissues, spleen, lymph nodes, peripheral blood lymphocytes and colonic mucosa (PubMed:11110709, PubMed:16809771). Expressed in macrophages (PubMed:27796300). Also expressed in nonhematopoietic tissues such as heart and skeletal muscle (PubMed:11110709, PubMed:16809771). Isoform 2 is the predominant form (PubMed:11110709). Most abundantly expressed in lymphomas with a brisk host inflammatory response (PubMed:11110709, PubMed:16809771). In diffuse large B-cell lymphomas tumors, expressed specifically by malignant B-cells (PubMed:11110709, PubMed:16809771).3 Publications

    Inductioni

    Up-regulated by IFNG in macrophages and in B-cell lymphoma cell lines (PubMed:16809771, PubMed:27796300, PubMed:26479788). Up-regulated by IFNB1 or viral infection (PubMed:26479788). Down-regulated by IL4 in macrophages (PubMed:27796300).3 Publications

    Gene expression databases

    BgeeiENSG00000138496.
    CleanExiHS_PARP9.
    ExpressionAtlasiQ8IXQ6. baseline and differential.
    GenevisibleiQ8IXQ6. HS.

    Organism-specific databases

    HPAiHPA066708.

    Interactioni

    Subunit structurei

    Forms a stable complex with E3 ligase DTX3L; the interaction is required for PARP9 mediated ADP-ribosylation of ubiquitin (PubMed:12670957, PubMed:28525742). Interacts (via PARP catalytic domain) with DTX3L (via N-terminus) (PubMed:26479788). Forms a complex with STAT1 and DTX3L independently of IFNB1 or IFNG-mediated STAT1 'Tyr-701' phosphorylation (PubMed:26479788). Forms a complex with STAT1, DTX3L and histone H2B HIST1H2BH/H2BJ; the interaction is likely to induce HIST1H2BH/H2BJ ubiquitination (PubMed:26479788). Interacts (via N-terminus) with STAT1 (PubMed:26479788). Interacts with PARP14 in IFNG-stimulated macrophages; the interaction prevents PARP14-mediated STAT1 and STAT6 ADP-riboslylation (PubMed:27796300). Interacts with PARP1 (when poly-ADP-ribosylated) (PubMed:23230272).5 Publications

    GO - Molecular functioni

    • enzyme binding Source: UniProtKB
    • histone binding Source: UniProtKB
    • STAT family protein binding Source: UniProtKB
    • ubiquitin-like protein ligase binding Source: UniProtKB

    Protein-protein interaction databases

    BioGridi123723. 11 interactors.
    IntActiQ8IXQ6. 1 interactor.
    STRINGi9606.ENSP00000353512.

    Structurei

    Secondary structure

    1854
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi311 – 314Combined sources4
    Beta strandi317 – 324Combined sources8
    Helixi326 – 328Combined sources3
    Beta strandi330 – 339Combined sources10
    Helixi347 – 356Combined sources10
    Helixi358 – 370Combined sources13
    Beta strandi378 – 382Combined sources5
    Beta strandi386 – 395Combined sources10
    Helixi402 – 419Combined sources18
    Beta strandi423 – 427Combined sources5
    Beta strandi433 – 437Combined sources5
    Helixi439 – 456Combined sources18
    Beta strandi462 – 468Combined sources7
    Helixi473 – 490Combined sources18

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    5AILX-ray1.55A/B310-493[»]
    ProteinModelPortaliQ8IXQ6.
    SMRiQ8IXQ6.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini107 – 296Macro 1PROSITE-ProRule annotationAdd BLAST190
    Domaini306 – 487Macro 2PROSITE-ProRule annotationAdd BLAST182
    Domaini628 – 850PARP catalyticPROSITE-ProRule annotationAdd BLAST223

    Domaini

    Macro domains 1 and 2 may be involved in the binding to poly(ADP-ribose) (PubMed:28525742, PubMed:26479788). Macro domain 2 is required for recruitment to DNA damage sites (PubMed:23230272). Macro domains 1 and 2 are probably dispensable for the interaction with STAT1 and DTX3L and for STAT1 phosphorylation (PubMed:26479788).3 Publications

    Keywords - Domaini

    Repeat

    Phylogenomic databases

    eggNOGiKOG2633. Eukaryota.
    COG2110. LUCA.
    GeneTreeiENSGT00760000119084.
    HOGENOMiHOG000115452.
    HOVERGENiHBG045406.
    InParanoidiQ8IXQ6.
    KOiK15260.
    OMAiSGIFQFP.
    OrthoDBiEOG091G02AK.
    PhylomeDBiQ8IXQ6.
    TreeFamiTF328965.

    Family and domain databases

    InterProiView protein in InterPro
    IPR002589. Macro_dom.
    IPR012317. Poly(ADP-ribose)pol_cat_dom.
    PfamiView protein in Pfam
    PF01661. Macro. 2 hits.
    SMARTiView protein in SMART
    SM00506. A1pp. 2 hits.
    PROSITEiView protein in PROSITE
    PS51154. MACRO. 2 hits.
    PS51059. PARP_CATALYTIC. 1 hit.

    Sequences (3)i

    Sequence statusi: Complete.

    This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: Q8IXQ6-1) [UniParc]FASTAAdd to basket
    Also known as: Long, L

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MDFSMVAGAA AYNEKSGRIT SLSLLFQKVF AQIFPQWRKG NTEECLPYKC
    60 70 80 90 100
    SETGALGENY SWQIPINHND FKILKNNERQ LCEVLQNKFG CISTLVSPVQ
    110 120 130 140 150
    EGNSKSLQVF RKMLTPRIEL SVWKDDLTTH AVDAVVNAAN EDLLHGGGLA
    160 170 180 190 200
    LALVKAGGFE IQEESKQFVA RYGKVSAGEI AVTGAGRLPC KQIIHAVGPR
    210 220 230 240 250
    WMEWDKQGCT GKLQRAIVSI LNYVIYKNTH IKTVAIPALS SGIFQFPLNL
    260 270 280 290 300
    CTKTIVETIR VSLQGKPMMS NLKEIHLVSN EDPTVAAFKA ASEFILGKSE
    310 320 330 340 350
    LGQETTPSFN AMVVNNLTLQ IVQGHIEWQT ADVIVNSVNP HDITVGPVAK
    360 370 380 390 400
    SILQQAGVEM KSEFLATKAK QFQRSQLVLV TKGFNLFCKY IYHVLWHSEF
    410 420 430 440 450
    PKPQILKHAM KECLEKCIEQ NITSISFPAL GTGNMEIKKE TAAEILFDEV
    460 470 480 490 500
    LTFAKDHVKH QLTVKFVIFP TDLEIYKAFS SEMAKRSKML SLNNYSVPQS
    510 520 530 540 550
    TREEKRENGL EARSPAINLM GFNVEEMYEA HAWIQRILSL QNHHIIENNH
    560 570 580 590 600
    ILYLGRKEHD ILSQLQKTSS VSITEIISPG RTELEIEGAR ADLIEVVMNI
    610 620 630 640 650
    EDMLCKVQEE MARKKERGLW RSLGQWTIQQ QKTQDEMKEN IIFLKCPVPP
    660 670 680 690 700
    TQELLDQKKQ FEKCGLQVLK VEKIDNEVLM AAFQRKKKMM EEKLHRQPVS
    710 720 730 740 750
    HRLFQQVPYQ FCNVVCRVGF QRMYSTPCDP KYGAGIYFTK NLKNLAEKAK
    760 770 780 790 800
    KISAADKLIY VFEAEVLTGF FCQGHPLNIV PPPLSPGAID GHDSVVDNVS
    810 820 830 840 850
    SPETFVIFSG MQAIPQYLWT CTQEYVQSQD YSSGPMRPFA QHPWRGFASG

    SPVD
    Length:854
    Mass (Da):96,343
    Last modified:October 10, 2003 - v2
    Checksum:iCBBB3B4B7CA1CDA4
    GO
    Isoform 2 (identifier: Q8IXQ6-2) [UniParc]FASTAAdd to basket
    Also known as: Short, S

    The sequence of this isoform differs from the canonical sequence as follows:
         17-51: Missing.

    Show »
    Length:819
    Mass (Da):92,271
    Checksum:i110B81666B857940
    GO
    Isoform 3 (identifier: Q8IXQ6-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         17-51: Missing.
         729-745: DPKYGAGIYFTKNLKNL → GRCQCLIIGATLWNLVS
         746-854: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:710
    Mass (Da):80,291
    Checksum:iE443D3E78BDF0E53
    GO

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti487S → P in BAF85648 (PubMed:14702039).Curated1
    Sequence conflicti839F → S in BAG36276 (PubMed:14702039).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_05665421S → L. Corresponds to variant dbSNP:rs34006803Ensembl.1
    Natural variantiVAR_056655517I → V1 PublicationCorresponds to variant dbSNP:rs28365795Ensembl.1
    Natural variantiVAR_056656528Y → C3 PublicationsCorresponds to variant dbSNP:rs9851180Ensembl.1
    Natural variantiVAR_056657651T → A. Corresponds to variant dbSNP:rs6780543Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_00850517 – 51Missing in isoform 2 and isoform 3. 3 PublicationsAdd BLAST35
    Alternative sequenceiVSP_046086729 – 745DPKYG…NLKNL → GRCQCLIIGATLWNLVS in isoform 3. 1 PublicationAdd BLAST17
    Alternative sequenceiVSP_046087746 – 854Missing in isoform 3. 1 PublicationAdd BLAST109

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF307338 mRNA. Translation: AAK07558.1.
    AF307339 mRNA. Translation: AAK07559.1.
    AK292959 mRNA. Translation: BAF85648.1.
    AK313494 mRNA. Translation: BAG36276.1.
    AC092908 Genomic DNA. No translation available.
    AC096861 Genomic DNA. No translation available.
    BC017463 mRNA. No translation available.
    BC039580 mRNA. Translation: AAH39580.1.
    AL713679 mRNA. Translation: CAD28483.1.
    CCDSiCCDS3014.1. [Q8IXQ6-1]
    CCDS54633.1. [Q8IXQ6-3]
    CCDS54634.1. [Q8IXQ6-2]
    RefSeqiNP_001139574.1. NM_001146102.1. [Q8IXQ6-1]
    NP_001139575.1. NM_001146103.1. [Q8IXQ6-2]
    NP_001139576.1. NM_001146104.1. [Q8IXQ6-2]
    NP_001139577.1. NM_001146105.1. [Q8IXQ6-2]
    NP_113646.2. NM_031458.2. [Q8IXQ6-1]
    XP_005247877.1. XM_005247820.2. [Q8IXQ6-1]
    XP_016862793.1. XM_017007304.1. [Q8IXQ6-1]
    XP_016862794.1. XM_017007305.1. [Q8IXQ6-2]
    XP_016862795.1. XM_017007306.1. [Q8IXQ6-2]
    UniGeneiHs.518200.

    Genome annotation databases

    EnsembliENST00000360356; ENSP00000353512; ENSG00000138496. [Q8IXQ6-1]
    ENST00000462315; ENSP00000418894; ENSG00000138496. [Q8IXQ6-3]
    ENST00000471785; ENSP00000419001; ENSG00000138496. [Q8IXQ6-2]
    ENST00000477522; ENSP00000419506; ENSG00000138496. [Q8IXQ6-2]
    GeneIDi83666.
    KEGGihsa:83666.
    UCSCiuc003efh.5. human. [Q8IXQ6-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Entry informationi

    Entry nameiPARP9_HUMAN
    AccessioniPrimary (citable) accession number: Q8IXQ6
    Secondary accession number(s): A8KA94
    , B2R8S9, E9PFM7, Q8TCP3, Q9BZL8, Q9BZL9
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 10, 2003
    Last sequence update: October 10, 2003
    Last modified: November 22, 2017
    This is version 127 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 3
      Human chromosome 3: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references