Proliferating cell nuclear antigen

The assembled human DNA clamp, a trimer of the protein PCNA.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1AXC, 1U76, 1U7B, 1UL1, 1VYJ, 1VYM, 1W60, 2ZVK, 2ZVL, 2ZVM, 3P87, 3TBL, 3VKX, 3WGW, 4D2G

Identifiers

Symbols

PCNA ; ATLD2

External IDs

OMIM: 176740 MGI: 97503 HomoloGene: 1945 GeneCards: PCNA Gene

Gene ontology
Molecular function	• purine-specific mismatch base pair DNA N-glycosylase activity • chromatin binding • damaged DNA binding • protein binding • estrogen receptor binding • DNA polymerase processivity factor activity • receptor tyrosine kinase binding • dinucleotide insertion or deletion binding • MutLalpha complex binding • histone acetyltransferase binding • identical protein binding • DNA polymerase binding
Cellular component	• nucleus • nucleoplasm • DNA replication factor C complex • cytoplasm • centrosome • nuclear replication fork • PCNA complex • extracellular exosome • PCNA-p21 complex
Biological process	• G1/S transition of mitotic cell cycle • regulation of transcription involved in G1/S transition of mitotic cell cycle • mitotic cell cycle • telomere maintenance via recombination • telomere maintenance • DNA strand elongation involved in DNA replication • leading strand elongation • DNA repair • transcription-coupled nucleotide-excision repair • base-excision repair • nucleotide-excision repair • nucleotide-excision repair, DNA gap filling • mismatch repair • heart development • cell proliferation • translesion synthesis • epithelial cell differentiation • positive regulation of deoxyribonuclease activity • telomere maintenance via semi-conservative replication • response to lipid • cellular response to UV • error-prone translesion synthesis • DNA damage response, detection of DNA damage • positive regulation of DNA repair • positive regulation of DNA replication • response to cadmium ion • error-free translesion synthesis
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 20:
5.11 – 5.13 Mb

Chr 2:
132.25 – 132.25 Mb

PubMed search

Proliferating cell nuclear antigen (PCNA) is a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells and is essential for replication. PCNA is a homotrimer and achieves its processivity by encircling the DNA, where it acts as a scaffold to recruit proteins involved in DNA replication, DNA repair, chromatin remodeling and epigenetics.^[1]

Many proteins interact with PCNA via the two known PCNA-interacting motifs PCNA-interacting peptide (PIP) box ^[2] and AlkB homologue 2 PCNA interacting motif (APIM).^[3] Proteins binding to PCNA via the PIP-box are mainly involved in DNA replication whereas proteins binding to PCNA via APIM are mainly important in the context of genotoxic stress.^[4]

Function

The protein encoded by this gene is found in the nucleus and is a cofactor of DNA polymerase delta. The encoded protein acts as a homotrimer and helps increase the processivity of leading strand synthesis during DNA replication. In response to DNA damage, this protein is ubiquitinated and is involved in the RAD6-dependent DNA repair pathway. Two transcript variants encoding the same protein have been found for this gene. Pseudogenes of this gene have been described on chromosome 4 and on the X chromosome.^[5]

Expression in the nucleus during DNA synthesis

PCNA was originally identified as an antigen that is expressed in the nuclei of cells during the DNA synthesis phase of the cell cycle.^[6] Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone.^[7] PCNA helps hold DNA polymerase epsilon (Pol ε) to DNA. PCNA is clamped^[8] to DNA through the action of replication factor C (RFC),^[9] which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2F transcription factor-containing complexes.^[10]

Role in DNA repair

Since DNA polymerase epsilon is involved in resynthesis of excised damaged DNA strands during DNA repair, PCNA is important for both DNA synthesis and DNA repair.^[11]^[12]

PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair (PRR).^[13] In PRR, there are two sub-pathways: (1) a translesion pathway, which is carried out by specialised DNA polymerases that are able to incorporate damaged DNA bases into their active sites (unlike the normal replicative polymerase, which stall), and hence bypass the damage, and (2) a proposed "template switch" pathway that is thought to involve damage bypass by recruitment of the homologous recombination machinery. PCNA is pivotal to the activation of these pathways and the choice as to which pathway is utilised by the cell. PCNA becomes post-translationally modified by ubiquitin.^[14] Mono-ubiquitin of lysine number 164 on PCNA activates the translesion synthesis pathway. Extension of this mono-ubiquitin by a non-canonical lysine-63-linked poly-ubiquitin chain on PCNA^[14] is thought to activate the template switch pathway. Furthermore, sumoylation (by small ubiquitin-like modifier, SUMO) of PCNA lysine-164 (and to a lesser extent, lysine-127) inhibits the template switch pathway.^[14] This antagonistic effect occurs because sumoylated PCNA recruits a DNA helicase called Srs2,^[15] which has a role in disrupting Rad51 nucleoprotein filaments fundamental for initiation of homologous recombination.

PCNA-binding proteins

• TCP protein domain • NKp44 Receptor • procaspases ^[16] • DNA polymerases • Clamp loader • Flap endonuclease • DNA ligase • Topoisomerase • Replication licensing factor • E3 ubiquitin ligases • E2 SUMO-conjugating enzyme • Helicases, ATPases • Mismatch repair enzymes • Base excision repair enzymes • Nucleotide excision repair enzyme • Poly ADP ribose polymerase • Histone chaperone • Chromatin remodeling factor • Histone acetyltransferase • Histone deacetyltransferase • DNA methyltransferase • Sister-chromatid cohesion factors • Protein kinases • Cell-cycle regulators • Apoptotic factors

for details see^[17]

Interactions

PCNA has been shown to interact with:

Annexin A2,^[18]
CDC25C,^[19]
CHTF18,^[18]
Cyclin D1,^[20]^[21]
Cyclin O,^[18]^[22]
Cyclin-dependent kinase 4,^[21]^[23]
Cyclin-dependent kinase inhibitor 1C,^[24]
DNMT1,^[25]^[26]^[27]
EP300,^[28]
Flap structure-specific endonuclease 1,^[29]^[30]^[31]^[32]^[33]^[34]^[35]
GADD45A,^[36]^[37]^[38]^[39]^[40]
GADD45G,^[41]^[42]
HDAC1,^[43]
HUS1,^[44]
ING1,^[45]
KCTD13,^[46]
KIAA0101,^[35]
Ku70,^[18]^[47]
Ku80,^[18]^[47]^[48]
MCL1,^[49]
MSH3,^[18]^[50]^[51]
MSH6,^[18]^[50]^[51]
MUTYH,^[52]
P21,^[24]^[31]^[35]^[53]^[54]^[55]^[56]^[57]
POLD2,^[58]
POLD3,^[18]^[59]
POLDIP2,^[60]
POLH,^[61]
POLL,^[62]^[63]^[64]
RFC1,^[18]^[53]^[65]^[66]^[67]
RFC2,^[18]^[68]^[69]
RFC3,^[18]^[70]
RFC4,^[18]^[68]
RFC5,^[18]^[66]^[68]
Ubiquitin C^[71]^[72]^[73]
Werner syndrome ATP-dependent helicase,^[74]^[75]
XRCC1,^[76] and
Y box binding protein 1.^[77]

Proteins interacting with PCNA via APIM include human AlkB homologue 2, TFIIS-L, TFII-I, Rad51B,^[3] XPA,^[78] ZRANB3,^[79] and FBH1.^[80]

Uses

Antibodies against proliferating cell nuclear antigen (PCNA) or monoclonal antibody termed Ki-67 can be used for grading of different neoplasms, e.g. astrocytoma. They can be of diagnostic and prognostic value. Imaging of the nuclear distribution of PCNA (via antibody labeling) can be used to distinguish between early, mid and late S phase of the cell cycle.^[81] However, an important limitation of antibodies is that cells need to be fixed leading to potential artifacts.

On the other hand, the study of the dynamics of replication and repair in living cells can be done introducing translational fusions of PCNA. To obviate the need for transfection and bypass the problem of difficult to transfect and/or short lived cells, cell permeable replication and/or repair markers can be used. These peptides offer the distinct advantage that can be used in situ in living tissue and even distinguish cells undergoing replication from cells undergoing repair.^[82]

PCNA is a potential therapeutic target in cancer therapy.^[83]

External links

PCNA at the US National Library of Medicine Medical Subject Headings (MeSH)
"ANA: Cell cycle related (Mitotic): PCNA type 1 and type 2 Antibody Patterns". Antibody Patterns.com. Retrieved 2008-04-15.
Dan Krotz. "Structure of a clamp–loader complex". Advanced Light Source News. Lawrence Berkeley National Laboratory. Retrieved 2008-04-15. ^[8]
"Movie showing a model of clamp loading of PCNA onto DNA". Pubmed Central. ^[84]

References

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↑ Warbrick E (Mar 1998). "PCNA binding through a conserved motif.". BioEssays : news and reviews in molecular, cellular and developmental biology 20 (3): 195–9. doi:10.1002/(sici)1521-1878(199803)20:3<195::aid-bies2>3.0.co;2-r. PMID 9631646.
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↑ Mailand N, Gibbs-Seymour I, Bekker-Jensen S (May 2013). "Regulation of PCNA-protein interactions for genome stability.". Nature reviews. Molecular cell biology 14 (5): 269–82. doi:10.1038/nrm3562. PMID 23594953.
↑ "Entrez Gene: PCNA proliferating cell nuclear antigen".
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1 2 3 4 5 6 7 8 9 10 11 12 13 Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T (October 2002). "A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein". J. Biol. Chem. 277 (43): 40362–7. doi:10.1074/jbc.M206194200. PMID 12171929.
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↑ Vairapandi M, Azam N, Balliet AG, Hoffman B, Liebermann DA (June 2000). "Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 AND Gadd45-mediated negative growth control". J. Biol. Chem. 275 (22): 16810–9. doi:10.1074/jbc.275.22.16810. PMID 10828065.
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1 2 Kleczkowska HE, Marra G, Lettieri T, Jiricny J (March 2001). "hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci". Genes Dev. 15 (6): 724–36. doi:10.1101/gad.191201. PMC 312660. PMID 11274057.
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1 2 Fotedar R, Mossi R, Fitzgerald P, Rousselle T, Maga G, Brickner H, Messier H, Kasibhatla S, Hübscher U, Fotedar A (August 1996). "A conserved domain of the large subunit of replication factor C binds PCNA and acts like a dominant negative inhibitor of DNA replication in mammalian cells". EMBO J. 15 (16): 4423–33. PMC 452166. PMID 8861969.
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↑ Lu X, Tan CK, Zhou JQ, You M, Carastro LM, Downey KM, So AG (July 2002). "Direct interaction of proliferating cell nuclear antigen with the small subunit of DNA polymerase delta". J. Biol. Chem. 277 (27): 24340–5. doi:10.1074/jbc.M200065200. PMID 11986310.
↑ Ducoux M, Urbach S, Baldacci G, Hübscher U, Koundrioukoff S, Christensen J, Hughes P (December 2001). "Mediation of proliferating cell nuclear antigen (PCNA)-dependent DNA replication through a conserved p21(Cip1)-like PCNA-binding motif present in the third subunit of human DNA polymerase delta". J. Biol. Chem. 276 (52): 49258–66. doi:10.1074/jbc.M106990200. PMID 11595739.
↑ Liu L, Rodriguez-Belmonte EM, Mazloum N, Xie B, Lee MY (March 2003). "Identification of a novel protein, PDIP38, that interacts with the p50 subunit of DNA polymerase delta and proliferating cell nuclear antigen". J. Biol. Chem. 278 (12): 10041–7. doi:10.1074/jbc.M208694200. PMID 12522211.
↑ Haracska L, Johnson RE, Unk I, Phillips B, Hurwitz J, Prakash L, Prakash S (November 2001). "Physical and functional interactions of human DNA polymerase eta with PCNA". Mol. Cell. Biol. 21 (21): 7199–206. doi:10.1128/MCB.21.21.7199-7206.2001. PMC 99895. PMID 11585903.
↑ Haracska L, Unk I, Johnson RE, Phillips BB, Hurwitz J, Prakash L, Prakash S (February 2002). "Stimulation of DNA synthesis activity of human DNA polymerase kappa by PCNA". Mol. Cell. Biol. 22 (3): 784–91. doi:10.1128/mcb.22.3.784-791.2002. PMC 133560. PMID 11784855.
↑ Maga G, Villani G, Ramadan K, Shevelev I, Tanguy Le Gac N, Blanco L, Blanca G, Spadari S, Hübscher U (December 2002). "Human DNA polymerase lambda functionally and physically interacts with proliferating cell nuclear antigen in normal and translesion DNA synthesis". J. Biol. Chem. 277 (50): 48434–40. doi:10.1074/jbc.M206889200. PMID 12368291.
↑ Shimazaki N, Yoshida K, Kobayashi T, Toji S, Tamai K, Koiwai O (July 2002). "Over-expression of human DNA polymerase lambda in E. coli and characterization of the recombinant enzyme". Genes Cells 7 (7): 639–51. doi:10.1046/j.1365-2443.2002.00547.x. PMID 12081642.
↑ Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K (September 2002). "A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase". Mol. Cell. Biol. 22 (18): 6509–20. doi:10.1128/mcb.22.18.6509-6520.2002. PMC 135621. PMID 12192049.
1 2 Mossi R, Jónsson ZO, Allen BL, Hardin SH, Hübscher U (January 1997). "Replication factor C interacts with the C-terminal side of proliferating cell nuclear antigen". J. Biol. Chem. 272 (3): 1769–76. doi:10.1074/jbc.272.3.1769. PMID 8999859.
↑ van der Kuip H, Carius B, Haque SJ, Williams BR, Huber C, Fischer T (April 1999). "The DNA-binding subunit p140 of replication factor C is upregulated in cycling cells and associates with G1 phase cell cycle regulatory proteins". J. Mol. Med. 77 (4): 386–92. doi:10.1007/s001090050365. PMID 10353443.
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↑ Pan ZQ, Chen M, Hurwitz J (January 1993). "The subunits of activator 1 (replication factor C) carry out multiple functions essential for proliferating-cell nuclear antigen-dependent DNA synthesis". Proc. Natl. Acad. Sci. U.S.A. 90 (1): 6–10. doi:10.1073/pnas.90.1.6. PMC 45588. PMID 8093561.
↑ Merkle CJ, Karnitz LM, Henry-Sánchez JT, Chen J (August 2003). "Cloning and characterization of hCTF18, hCTF8, and hDCC1. Human homologs of a Saccharomyces cerevisiae complex involved in sister chromatid cohesion establishment". J. Biol. Chem. 278 (32): 30051–6. doi:10.1074/jbc.M211591200. PMID 12766176.
↑ Motegi A, Liaw HJ, Lee KY, Roest HP, Maas A, Wu X, Moinova H, Markowitz SD, Ding H, Hoeijmakers JH, Myung K (August 2008). "Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks". Proc. Natl. Acad. Sci. U.S.A. 105 (34): 12411–6. doi:10.1073/pnas.0805685105. PMC 2518831. PMID 18719106.
↑ Unk I, Hajdú I, Fátyol K, Hurwitz J, Yoon JH, Prakash L, Prakash S, Haracska L (March 2008). "Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination". Proc. Natl. Acad. Sci. U.S.A. 105 (10): 3768–73. doi:10.1073/pnas.0800563105. PMC 2268824. PMID 18316726.
↑ Brun J, Chiu R, Lockhart K, Xiao W, Wouters BG, Gray DA (2008). "hMMS2 serves a redundant role in human PCNA polyubiquitination". BMC Mol. Biol. 9: 24. doi:10.1186/1471-2199-9-24. PMC 2263069. PMID 18284681.
↑ Rodríguez-López AM, Jackson DA, Nehlin JO, Iborra F, Warren AV, Cox LS (February 2003). "Characterisation of the interaction between WRN, the helicase/exonuclease defective in progeroid Werner's syndrome, and an essential replication factor, PCNA". Mech. Ageing Dev. 124 (2): 167–74. doi:10.1016/s0047-6374(02)00131-8. PMID 12633936.
↑ Huang S, Beresten S, Li B, Oshima J, Ellis NA, Campisi J (June 2000). "Characterization of the human and mouse WRN 3'-->5' exonuclease". Nucleic Acids Res. 28 (12): 2396–405. doi:10.1093/nar/28.12.2396. PMC 102739. PMID 10871373.
↑ Fan J, Otterlei M, Wong HK, Tomkinson AE, Wilson DM. "XRCC1 co-localizes and physically interacts with PCNA". Nucleic Acids Res. 32 (7): 2193–201. doi:10.1093/nar/gkh556. PMC 407833. PMID 15107487.
↑ Ise T, Nagatani G, Imamura T, Kato K, Takano H, Nomoto M, Izumi H, Ohmori H, Okamoto T, Ohga T, Uchiumi T, Kuwano M, Kohno K (January 1999). "Transcription factor Y-box binding protein 1 binds preferentially to cisplatin-modified DNA and interacts with proliferating cell nuclear antigen". Cancer Res. 59 (2): 342–6. PMID 9927044.
↑ Gilljam KM, Müller R, Liabakk NB, Otterlei M (2012). "Nucleotide excision repair is associated with the replisome and its efficiency depends on a direct interaction between XPA and PCNA.". PLoS ONE 7 (11): e49199. doi:10.1371/journal.pone.0049199. PMC 3496702. PMID 23152873.
↑ Ciccia A, Nimonkar AV, Hu Y, Hajdu I, Achar YJ, Izhar L, Petit SA, Adamson B, Yoon JC, Kowalczykowski SC, Livingston DM, Haracska L, Elledge SJ (Aug 10, 2012). "Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress.". Molecular Cell 47 (3): 396–409. doi:10.1016/j.molcel.2012.05.024. PMC 3613862. PMID 22704558.
↑ Bacquin A, Pouvelle C, Siaud N, Perderiset M, Salomé-Desnoulez S, Tellier-Lebegue C, Lopez B, Charbonnier JB, Kannouche PL (Jul 2013). "The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells.". Nucleic Acids Research 41 (13): 6501–13. doi:10.1093/nar/gkt397. PMC 3711418. PMID 23677613.
↑ Schönenberger F, Deutzmann A, Ferrando-May E, Merhof D (29 May 2015). "Discrimination of cell cycle phases in PCNA-immunolabeled cells". BMC Bioinform. 16 (180). doi:10.1186/s12859-015-0618-9. PMID 26022740.
↑ Herce HD, Rajan M, Lättig-Tünnemann G, Fillies M, Cardoso MC (3 September 2014). "A novel cell permeable DNA replication and repair marker.". Nucleus (Austin, Tex.) 5 (6): 590–600. doi:10.4161/nucl.36290. PMC 4615156. PMID 25484186.
↑ Wang SC (Apr 2014). "PCNA: a silent housekeeper or a potential therapeutic target?". Trends in pharmacological sciences 35 (4): 178–186. doi:10.1016/j.tips.2014.02.004. PMID 24655521.
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PDB gallery

1axc: HUMAN PCNA

1u76: Crystal structure of hPCNA bound to residues 452-466 of the DNA polymerase-delta-p66 subunit

1u7b: Crystal structure of hPCNA bound to residues 331-350 of the flap endonuclease-1 (FEN1)

1ul1: Crystal structure of the human FEN1-PCNA complex

1vyj: STRUCTURAL AND BIOCHEMICAL STUDIES OF HUMAN PCNA COMPLEXES PROVIDE THE BASIS FOR ASSOCIATION WITH CDK/CYCLIN AND RATIONALE FOR INHIBITOR DESIGN

1vym: NATIVE HUMAN PCNA

1w60: NATIVE HUMAN PCNA

Tumor markers

Blood

Lymphoma	Neprilysin

Lymphosarcoma	CD3 CD79a

Endocrine

Thyroid cancer	Thyroglobulin Medullary thyroid cancer (Calcitonin Carcinoembryonic antigen)

Pheochromocytoma	Normetanephrine Enolase 2

Neuroendocrine tumors	Synaptophysin Chromogranin A

Neuroblastoma	Homovanillic acid

Nervous system

Brain tumor	PCNA

Astrocytoma	Glial fibrillary acidic protein

NC/Melanoma	S100 protein Melanoma inhibitory activity

Cardiovascular/
respiratory

Lung cancer	Carcinoembryonic antigen Enolase 2 Autocrine motility factor

Hemangiosarcoma (endothelium)	Factor VIII

Digestive

Colorectal cancer	CA19-9 Carcinoembryonic antigen

Pancreatic cancer	CA19-9 Carcinoembryonic antigen CA 242 Tumor-associated glycoprotein 72

Hepatocellular carcinoma	Alpha-fetoprotein/AFP-L3

Reproductive/
urinary/
breast

Ovarian tumor	Surface epithelial-stromal tumor CA-125 EC CD30 hCG EST Alpha-fetoprotein Choriocarcinoma hCG Dysgerminoma LDH Sertoli-Leydig cell tumour Testosterone GCT Inhibin

Testicular cancer	βhCG Alpha-fetoprotein/AFP-L3 CD30

Prostate cancer	Prostate-specific antigen Prostatic acid phosphatase Glutamate carboxypeptidase II erbB-3 receptor Early prostate cancer antigen-2 SPINK1 GOLM1 PCA3 TMPRSS2

Germ cell tumor	NANOG

Bladder cancer	erbB-3 receptor NMP22

Breast cancer	CA 15-3 erbB-2 receptor erbB-3 receptor Cathepsin D Ca 27-29

General histology

Sarcoma	Vimentin

Carcinoma (epithelium)	Cytokeratin

Musculoskeletal

Rhabdomyosarcoma	Desmin

DNA replication (comparing Prokaryotic to Eukaryotic)

Initiation

Prokaryotic (initiation)	Pre-replication complex dnaC Cdc6 Helicase dnaA dnaB T7 Primase dnaG

Eukaryotic (preparation in G1 phase)	Pre-replication complex Origin recognition complex ORC1 ORC2 ORC3 ORC4 ORC5 ORC6 Cdc6 Cdt1 Minichromosome maintenance MCM2 MCM3 MCM4 MCM5 MCM6 MCM7 Licensing factor Autonomously replicating sequence Single-strand binding protein SSBP2 SSBP3 SSBP4 RNase H RNASEH1 RNASEH2A Helicase: HFM1 Primase: PRIM1 PRIM2

Both	Origin of replication/Ori/Replicon Replication fork Lagging and leading strands Okazaki fragments Primer

Replication

Prokaryotic (elongation)	DNA polymerase III holoenzyme dnaC dnaE dnaH dnaN dnaQ dnaT dnaX holA holB holC holD holE Replisome DNA ligase DNA clamp Topoisomerase DNA gyrase Prokaryotic DNA polymerase: DNA polymerase I Klenow fragment

Eukaryotic (synthesis in S phase)	Replication factor C RFC1 Flap endonuclease FEN1 Topoisomerase Replication protein A RPA1 Eukaryotic DNA polymerase: alpha POLA1 POLA2 PRIM1 PRIM2 delta POLD1 POLD2 POLD3 POLD4 epsilon POLE POLE2 POLE3 POLE4 DNA clamp PCNA Control of chromosome duplication

Both	Movement: Processivity DNA ligase

Termination

Telomere: Telomerase
- TERT
- TERC
- DKC1

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