Proliferating cell nuclear antigen

Proliferating cell nuclear antigen
The assembled human DNA clamp, a trimer of the protein PCNA.
Available structures PDB 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
Entrez	5111	18538
Ensembl	ENSG00000132646	ENSMUSG00000027342
UniProt	P12004	P17918
RefSeq (mRNA)	NM_002592	NM_011045
RefSeq (protein)	NP_002583	NP_035175
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 eliminate 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]

See also

• Transcription
• Ki-67 – cellular marker for proliferation

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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Further reading

• Prosperi E (1998). "Multiple roles of the proliferating cell nuclear antigen: DNA replication, repair and cell cycle control". Progress in cell cycle research 3: 193–210. doi:10.1007/978-1-4615-5371-7_15. PMID 9552415.
• Miura M (1999). "Detection of chromatin-bound PCNA in mammalian cells and its use to study DNA excision repair". J. Radiat. Res. 40 (1): 1–12. doi:10.1269/jrr.40.1. PMID 10408173.
• Chen M, Pan ZQ, Hurwitz J (1992). "Sequence and expression in Escherichia coli of the 40-kDa subunit of activator 1 (replication factor C) of HeLa cells". Proc. Natl. Acad. Sci. U.S.A. 89 (7): 2516–2520. doi:10.1073/pnas.89.7.2516. PMC 48692. PMID 1313560.
• Kemeny MM, Alava G, Oliver JM (1993). "Improving responses in hepatomas with circadian-patterned hepatic artery infusions of recombinant interleukin-2". J. Immunother. 12 (4): 219–223. doi:10.1097/00002371-199211000-00001. PMID 1477073.
• Morris GF, Mathews MB (1990). "Analysis of the proliferating cell nuclear antigen promoter and its response to adenovirus early region 1". J. Biol. Chem. 265 (27): 16116–25. PMID 1975809.
• Webb G, Parsons P, Chenevix-Trench G (1991). "Localization of the gene for human proliferating nuclear antigen/cyclin by in situ hybridization". Hum. Genet. 86 (1): 84–6. doi:10.1007/bf00205180. PMID 1979311.
• Travali S, Ku DH, Rizzo MG, Ottavio L, Baserga R, Calabretta B (1989). "Structure of the human gene for the proliferating cell nuclear antigen". J. Biol. Chem. 264 (13): 7466–72. PMID 2565339.
• Ku DH, Travali S, Calabretta B, Huebner K, Baserga R (1989). "Human gene for proliferating cell nuclear antigen has pseudogenes and localizes to chromosome 20". Somat. Cell Mol. Genet. 15 (4): 297–307. doi:10.1007/BF01534969. PMID 2569765.
• Prelich G, Kostura M, Marshak DR, Mathews MB, Stillman B (1987). "The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro". Nature 326 (6112): 471–5. doi:10.1038/326471a0. PMID 2882422.
• Almendral JM, Huebsch D, Blundell PA, Macdonald-Bravo H, Bravo R (1987). "Cloning and sequence of the human nuclear protein cyclin: homology with DNA-binding proteins". Proc. Natl. Acad. Sci. U.S.A. 84 (6): 1575–9. doi:10.1073/pnas.84.6.1575. PMC 304478. PMID 2882507.
• Chen IT, Smith ML, O'Connor PM, Fornace AJ (1995). "Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA". Oncogene 11 (10): 1931–7. PMID 7478510.
• Li X, Li J, Harrington J, Lieber MR, Burgers PM (1995). "Lagging strand DNA synthesis at the eukaryotic replication fork involves binding and stimulation of FEN-1 by proliferating cell nuclear antigen". J. Biol. Chem. 270 (38): 22109–12. doi:10.1074/jbc.270.38.22109. PMID 7673186.
• Fukuda K, Morioka H, Imajou S, Ikeda S, Ohtsuka E, Tsurimoto T (1995). "Structure-function relationship of the eukaryotic DNA replication factor, proliferating cell nuclear antigen". J. Biol. Chem. 270 (38): 22527–34. doi:10.1074/jbc.270.38.22527. PMID 7673244.
• Warbrick E, Lane DP, Glover DM, Cox LS (1995). "A small peptide inhibitor of DNA replication defines the site of interaction between the cyclin-dependent kinase inhibitor p21WAF1 and proliferating cell nuclear antigen". Curr. Biol. 5 (3): 275–282. doi:10.1016/S0960-9822(95)00058-3. PMID 7780738.
• Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E, Cox LS (1995). "Characterisation of the interaction between PCNA and Gadd45". Oncogene 10 (12): 2427–33. PMID 7784094.
• Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N, Yokoyama-Kobayashi M, Aoki T (1995). "Construction of a human full-length cDNA bank". Gene 150 (2): 243–50. doi:10.1016/0378-1119(94)90433-2. PMID 7821789.
• Matsuoka S, Yamaguchi M, Matsukage A (1994). "D-type cyclin-binding regions of proliferating cell nuclear antigen". J. Biol. Chem. 269 (15): 11030–6. PMID 7908906.
• Szepesi A, Gelfand EW, Lucas JJ (1994). "Association of proliferating cell nuclear antigen with cyclin-dependent kinases and cyclins in normal and transformed human T lymphocytes". Blood 84 (10): 3413–21. PMID 7949095.
• Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ (1994). "Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen". Science 266 (5189): 1376–80. doi:10.1126/science.7973727. PMID 7973727.
• Pan ZQ, Chen M, Hurwitz J (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.