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Protein

Proliferating cell nuclear antigen

Gene

PCNA

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

Functioni

Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways (PubMed:24939902). Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion.3 Publications

Miscellaneous

Antibodies against PCNA are present in sera from patients with systemic lupus erythematosus.

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
DNA bindingi61 – 80Sequence analysisAdd BLAST20

GO - Molecular functioni

  • chromatin binding Source: UniProtKB
  • damaged DNA binding Source: UniProtKB
  • dinucleotide insertion or deletion binding Source: BHF-UCL
  • DNA polymerase binding Source: UniProtKB
  • DNA polymerase processivity factor activity Source: GO_Central
  • enzyme binding Source: BHF-UCL
  • estrogen receptor binding Source: Ensembl
  • histone acetyltransferase binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • MutLalpha complex binding Source: HGNC
  • purine-specific mismatch base pair DNA N-glycosylase activity Source: BHF-UCL
  • receptor tyrosine kinase binding Source: UniProtKB

GO - Biological processi

Keywordsi

Molecular functionDNA-binding
Biological processDNA damage, DNA repair, DNA replication, Host-virus interaction

Enzyme and pathway databases

ReactomeiR-HSA-110312 Translesion synthesis by REV1
R-HSA-110314 Recognition of DNA damage by PCNA-containing replication complex
R-HSA-110320 Translesion Synthesis by POLH
R-HSA-1362277 Transcription of E2F targets under negative control by DREAM complex
R-HSA-174411 Polymerase switching on the C-strand of the telomere
R-HSA-174414 Processive synthesis on the C-strand of the telomere
R-HSA-174417 Telomere C-strand (Lagging Strand) Synthesis
R-HSA-174437 Removal of the Flap Intermediate from the C-strand
R-HSA-4615885 SUMOylation of DNA replication proteins
R-HSA-5358565 Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)
R-HSA-5358606 Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)
R-HSA-539107 Activation of E2F1 target genes at G1/S
R-HSA-5651801 PCNA-Dependent Long Patch Base Excision Repair
R-HSA-5655862 Translesion synthesis by POLK
R-HSA-5656121 Translesion synthesis by POLI
R-HSA-5656169 Termination of translesion DNA synthesis
R-HSA-5685942 HDR through Homologous Recombination (HRR)
R-HSA-5696397 Gap-filling DNA repair synthesis and ligation in GG-NER
R-HSA-5696400 Dual Incision in GG-NER
R-HSA-6782135 Dual incision in TC-NER
R-HSA-6782210 Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-6804114 TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest
R-HSA-69091 Polymerase switching
R-HSA-69166 Removal of the Flap Intermediate
R-HSA-69183 Processive synthesis on the lagging strand
R-HSA-8866654 E3 ubiquitin ligases ubiquitinate target proteins
SignaLinkiP12004
SIGNORiP12004

Protein family/group databases

MoonDBiP12004 Predicted

Names & Taxonomyi

Protein namesi
Recommended name:
Proliferating cell nuclear antigen
Short name:
PCNA
Alternative name(s):
Cyclin
Gene namesi
Name:PCNA
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 20

Organism-specific databases

EuPathDBiHostDB:ENSG00000132646.10
HGNCiHGNC:8729 PCNA
MIMi176740 gene
neXtProtiNX_P12004

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

Nucleus

Pathology & Biotechi

Involvement in diseasei

Ataxia-telangiectasia-like disorder 2 (ATLD2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA neurodegenerative disorder due to defects in DNA excision repair. ATLD2 is characterized by developmental delay, ataxia, sensorineural hearing loss, short stature, cutaneous and ocular telangiectasia, and photosensitivity.
See also OMIM:615919
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071871228S → I in ATLD2; a hypomorphic mutation affecting DNA repair in response to UV; results in significantly decreased interaction with FEN1, LIG1 and ERCC5. 1 PublicationCorresponds to variant dbSNP:rs369958038EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi13K → R: Inhibits acetylation, recruitment to DNA damage sites, inducible ubiquitination and protein degradation, DNA replication and repair synthesis efficiencies, but homotrimer formation, nuclear recruitment to DNA damage sites, interactions with CREBBP, EP300 and POLD1 are similar as the wild-type; in association with R-14; R-20; R-77 and R-80. 1 Publication1
Mutagenesisi14K → R: Inhibits acetylation, recruitment to DNA damage sites, inducible ubiquitination and protein degradation, DNA replication and repair synthesis efficiencies, but homotrimer formation, nuclear recruitment to DNA damage sites, interactions with CREBBP, EP300 and POLD1 are similar as the wild-type; in association with R-13; R-20; R-77 and R-80. 1 Publication1
Mutagenesisi20K → R: Inhibits acetylation, recruitment to DNA damage sites, inducible ubiquitination and protein degradation, DNA replication and repair synthesis efficiencies, but homotrimer formation, nuclear recruitment to DNA damage sites, interactions with CREBBP, EP300 and POLD1 are similar as the wild-type; in association with R-13; R-14; R-77 and R-80. 1 Publication1
Mutagenesisi43 – 45SHV → AAA: No effect on POLD3-binding. 1 Publication3
Mutagenesisi77K → A: Inhibits recruitment to DNA damage sites, but nuclear localization is similar as the wild-type; in association with A-80. 1 Publication1
Mutagenesisi77K → R: Inhibits acetylation, recruitment to DNA damage sites, inducible ubiquitination and protein degradation, DNA replication and repair synthesis efficiencies, but homotrimer formation, nuclear recruitment to DNA damage sites, interactions with CREBBP, EP300 and POLD1 are similar as the wild-type; in association with R-13; R-14; R-20 and R-80. 1 Publication1
Mutagenesisi80K → A: Inhibits recruitment to DNA damage sites, but nuclear localization is similar as the wild-type; in association with A-77. 1 Publication1
Mutagenesisi80K → R: Inhibits acetylation, recruitment to DNA damage sites, inducible ubiquitination and protein degradation, DNA replication and repair synthesis efficiencies, but homotrimer formation, nuclear recruitment to DNA damage sites, interactions with CREBBP, EP300 and POLD1 are similar as the wild-type; in association with R-13; R-14; R-20 and R-77. 1 Publication1
Mutagenesisi125 – 128QLGI → AAAA: Strong decrease in POLD3-binding. 1 Publication4
Mutagenesisi164K → R: Abolishes ubiquitination. No effect on interaction with SHPRH. 4 Publications1
Mutagenesisi188 – 190VDK → AAA: No effect on POLD3-binding. 1 Publication3
Mutagenesisi211Y → F: Alters chromatin-associated PCNA stability and its function in DNA replication and repair. 1 Publication1
Mutagenesisi251 – 254LAPK → AAAA: Decrease in POLD3-binding. 1 Publication4

Keywords - Diseasei

Deafness, Disease mutation, Dwarfism, Neurodegeneration

Organism-specific databases

DisGeNETi5111
MalaCardsiPCNA
MIMi615919 phenotype
OpenTargetsiENSG00000132646
PharmGKBiPA263

Chemistry databases

ChEMBLiCHEMBL2346488

Polymorphism and mutation databases

BioMutaiPCNA
DMDMi129694

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001491581 – 261Proliferating cell nuclear antigenAdd BLAST261

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei14N6-acetyllysine1 Publication1
Modified residuei77N6-acetyllysineCombined sources1
Modified residuei80N6-acetyllysineCombined sources1
Cross-linki164Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateCombined sources
Cross-linki164Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate2 Publications
Modified residuei211Phosphotyrosine; by EGFR1 Publication1
Modified residuei248N6-acetyllysineCombined sources1
Cross-linki254Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources

Post-translational modificationi

Phosphorylated. Phosphorylation at Tyr-211 by EGFR stabilizes chromatin-associated PCNA.1 Publication
Acetylated by CREBBP and p300/EP300; preferentially acetylated by CREBBP on Lys-80, Lys-13 and Lys-14 and on Lys-77 by p300/EP300 upon loading on chromatin in response to UV irradiation (PubMed:24939902, PubMed:19419956). Lysine acetylation disrupts association with chromatin, hence promoting PCNA ubiquitination and proteasomal degradation in response to UV damage in a CREBBP- and EP300-dependent manner (PubMed:24939902). Acetylation disrupts interaction with NUDT15 and promotes degradation (PubMed:19419956).1 Publication
Ubiquitinated (PubMed:24939902, PubMed:20227374). Following DNA damage, can be either monoubiquitinated to stimulate direct bypass of DNA lesions by specialized DNA polymerases or polyubiquitinated to promote recombination-dependent DNA synthesis across DNA lesions by template switching mechanisms. Following induction of replication stress, monoubiquitinated by the UBE2B-RAD18 complex on Lys-164, leading to recruit translesion (TLS) polymerases, which are able to synthesize across DNA lesions in a potentially error-prone manner. An error-free pathway also exists and requires non-canonical polyubiquitination on Lys-164 through 'Lys-63' linkage of ubiquitin moieties by the E2 complex UBE2N-UBE2V2 and the E3 ligases, HLTF, RNF8 and SHPRH. This error-free pathway, also known as template switching, employs recombination mechanisms to synthesize across the lesion, using as a template the undamaged, newly synthesized strand of the sister chromatid. Monoubiquitination at Lys-164 also takes place in undamaged proliferating cells, and is mediated by the DCX(DTL) complex, leading to enhance PCNA-dependent translesion DNA synthesis. Sumoylated during S phase.10 Publications
Methylated on glutamate residues by ARMT1/C6orf211.1 Publication

Keywords - PTMi

Acetylation, Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiP12004
MaxQBiP12004
PaxDbiP12004
PeptideAtlasiP12004
PRIDEiP12004
ProteomicsDBi52816
TopDownProteomicsiP12004

2D gel databases

SWISS-2DPAGEiP12004

PTM databases

iPTMnetiP12004
PhosphoSitePlusiP12004
SwissPalmiP12004

Expressioni

Gene expression databases

BgeeiENSG00000132646
CleanExiHS_PCNA
GenevisibleiP12004 HS

Organism-specific databases

HPAiCAB000148
HPA030521
HPA030522
HPA030523

Interactioni

Subunit structurei

Homotrimer (PubMed:24939902). Interacts with p300/EP300; the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Interacts with CREBBP (via transactivation domain and C-terminus); the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Directly interacts with POLD1, POLD3 and POLD4 subunits of the DNA polymerase delta complex, POLD3 being the major interacting partner; the interaction with POLD3 is inhibited by CDKN1A/p21(CIP1) (PubMed:11595739, PubMed:16510448, PubMed:22148433, PubMed:24939902). Forms a complex with activator 1 heteropentamer in the presence of ATP. Interacts with EXO1, POLH, POLK, DNMT1, ERCC5, FEN1, CDC6 and POLDIP2 (PubMed:9305916, PubMed:9302295, PubMed:9566895, PubMed:11784855, PubMed:12522211, PubMed:15225546, PubMed:15149598, PubMed:24911150, PubMed:15616578). Interacts with APEX2; this interaction is triggered by reactive oxygen species and increased by misincorporation of uracil in nuclear DNA (PubMed:11376153, PubMed:19443450). Forms a ternary complex with DNTTIP2 and core histone (PubMed:12786946). Interacts with KCTD10 and PPP1R15A (By similarity). Directly interacts with BAZ1B (PubMed:15543136). Interacts with HLTF and SHPRH (PubMed:17130289, PubMed:18316726, PubMed:18719106). Interacts with NUDT15; this interaction is disrupted in response to UV irradiation and acetylation (PubMed:19419956). Interacts with CDKN1A/p21(CIP1) and CDT1; interacts via their PIP-box which also recruits the DCX(DTL) complex. The interaction with CDKN1A inhibits POLD3 binding (PubMed:11595739, PubMed:16949367, PubMed:18794347, PubMed:18703516). Interacts with DDX11 (PubMed:18499658). Interacts with EGFR; positively regulates PCNA (PubMed:17115032). Interacts with PARPBP (PubMed:22153967). Interacts (when ubiquitinated) with SPRTN; leading to enhance RAD18-mediated PCNA ubiquitination (PubMed:22681887). Interacts (when polyubiquitinated) with ZRANB3 (PubMed:22704558, PubMed:22705370, PubMed:22759634). Interacts with SMARCAD1 (PubMed:21549307). Interacts with CDKN1C (PubMed:22634751). Interacts with PCLAF (via PIP-box) (PubMed:21628590, PubMed:23000965). Interacts with RTEL1 (via PIP-box); the interaction is direct and essential for the suppression of telomere fragility (PubMed:24115439). Interacts with FAM111A (via PIP-box); the interaction is direct and required for PCNA loading on chromatin binding (PubMed:24561620). Interacts with LIG1 (PubMed:24911150). Interacts with SETMAR (PubMed:20457750). Interacts with ANKRD17 (PubMed:23711367). Interacts with FBXO18/FBH1 (via PIP-box); the interaction recruits the DCX(DTL) complex and promotes ubiquitination and degradation of FBXO18/FBH1 (PubMed:23677613). Interacts with POLN (PubMed:19995904). Interacts with SDE2 (via PIP-box); the interaction is direct and prevents ultraviolet light induced monoubiquitination (PubMed:27906959). Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR; interaction at least with PCNA occurs during DNA replication (PubMed:28191891). Interacts with MAPK15; the interaction is chromatin binding dependent and prevents MDM2-mediated PCNA destruction by inhibiting the association of PCNA with MDM2 (PubMed:20733054).By similarity44 Publications
(Microbial infection) Interacts with herpes virus 8 protein LANA1.1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

  • DNA polymerase binding Source: UniProtKB
  • enzyme binding Source: BHF-UCL
  • estrogen receptor binding Source: Ensembl
  • histone acetyltransferase binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • receptor tyrosine kinase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi111142, 299 interactors
ComplexPortaliCPX-538 PCNA homotrimer
CORUMiP12004
DIPiDIP-1098N
ELMiP12004
IntActiP12004, 131 interactors
MINTiP12004
STRINGi9606.ENSP00000368438

Chemistry databases

BindingDBiP12004

Structurei

Secondary structure

1261
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi2 – 7Combined sources6
Helixi10 – 20Combined sources11
Beta strandi24 – 31Combined sources8
Beta strandi34 – 40Combined sources7
Beta strandi44 – 53Combined sources10
Helixi54 – 56Combined sources3
Beta strandi57 – 64Combined sources8
Beta strandi66 – 71Combined sources6
Helixi72 – 79Combined sources8
Beta strandi87 – 92Combined sources6
Beta strandi94 – 96Combined sources3
Beta strandi97 – 104Combined sources8
Beta strandi106 – 109Combined sources4
Beta strandi111 – 117Combined sources7
Beta strandi121 – 126Combined sources6
Beta strandi134 – 140Combined sources7
Helixi141 – 152Combined sources12
Beta strandi156 – 163Combined sources8
Beta strandi166 – 173Combined sources8
Beta strandi176 – 182Combined sources7
Helixi191 – 193Combined sources3
Beta strandi196 – 201Combined sources6
Beta strandi203 – 208Combined sources6
Helixi209 – 215Combined sources7
Helixi216 – 221Combined sources6
Beta strandi223 – 229Combined sources7
Beta strandi231 – 233Combined sources3
Beta strandi235 – 241Combined sources7
Turni242 – 244Combined sources3
Beta strandi245 – 251Combined sources7

3D structure databases

ProteinModelPortaliP12004
SMRiP12004
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP12004

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni7 – 100Interaction with NUDT151 PublicationAdd BLAST94

Sequence similaritiesi

Belongs to the PCNA family.Curated

Phylogenomic databases

eggNOGiKOG1636 Eukaryota
COG0592 LUCA
GeneTreeiENSGT00390000004965
HOGENOMiHOG000211098
HOVERGENiHBG000947
InParanoidiP12004
KOiK04802
OMAiSDGFDKY
OrthoDBiEOG091G0GQ7
PhylomeDBiP12004
TreeFamiTF313441

Family and domain databases

HAMAPiMF_00317 DNApol_clamp_arch, 1 hit
InterProiView protein in InterPro
IPR000730 Pr_cel_nuc_antig
IPR022649 Pr_cel_nuc_antig_C
IPR022659 Pr_cel_nuc_antig_CS
IPR022648 Pr_cel_nuc_antig_N
PANTHERiPTHR11352:SF0 PTHR11352:SF0, 1 hit
PfamiView protein in Pfam
PF02747 PCNA_C, 1 hit
PF00705 PCNA_N, 1 hit
PRINTSiPR00339 PCNACYCLIN
TIGRFAMsiTIGR00590 pcna, 1 hit
PROSITEiView protein in PROSITE
PS01251 PCNA_1, 1 hit
PS00293 PCNA_2, 1 hit

Sequencei

Sequence statusi: Complete.

P12004-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MFEARLVQGS ILKKVLEALK DLINEACWDI SSSGVNLQSM DSSHVSLVQL
60 70 80 90 100
TLRSEGFDTY RCDRNLAMGV NLTSMSKILK CAGNEDIITL RAEDNADTLA
110 120 130 140 150
LVFEAPNQEK VSDYEMKLMD LDVEQLGIPE QEYSCVVKMP SGEFARICRD
160 170 180 190 200
LSHIGDAVVI SCAKDGVKFS ASGELGNGNI KLSQTSNVDK EEEAVTIEMN
210 220 230 240 250
EPVQLTFALR YLNFFTKATP LSSTVTLSMS ADVPLVVEYK IADMGHLKYY
260
LAPKIEDEEG S
Length:261
Mass (Da):28,769
Last modified:October 1, 1989 - v1
Checksum:iE6F08E7EDBC48B00
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071871228S → I in ATLD2; a hypomorphic mutation affecting DNA repair in response to UV; results in significantly decreased interaction with FEN1, LIG1 and ERCC5. 1 PublicationCorresponds to variant dbSNP:rs369958038EnsemblClinVar.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M15796 mRNA Translation: AAA35736.1
J04718 Genomic DNA Translation: AAA60040.1
AF527838 Genomic DNA Translation: AAM78556.1
AK313286 mRNA Translation: BAG36094.1
AL121924 Genomic DNA No translation available.
CH471133 Genomic DNA Translation: EAX10428.1
CH471133 Genomic DNA Translation: EAX10429.1
CH471133 Genomic DNA Translation: EAX10430.1
BC000491 mRNA Translation: AAH00491.1
BC062439 mRNA Translation: AAH62439.1
CCDSiCCDS13087.1
PIRiA27445 WMHUET
RefSeqiNP_002583.1, NM_002592.2
NP_872590.1, NM_182649.1
UniGeneiHs.147433
Hs.744934

Genome annotation databases

EnsembliENST00000379143; ENSP00000368438; ENSG00000132646
ENST00000379160; ENSP00000368458; ENSG00000132646
GeneIDi5111
KEGGihsa:5111
UCSCiuc002wlp.4 human

Similar proteinsi

Entry informationi

Entry nameiPCNA_HUMAN
AccessioniPrimary (citable) accession number: P12004
Secondary accession number(s): B2R897, D3DW02
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: October 1, 1989
Last modified: July 18, 2018
This is version 214 of the entry and version 1 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, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 20
    Human chromosome 20: 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
  6. SIMILARITY comments
    Index of protein domains and families

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