Proliferating cell nuclear antigen

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.^[5]

PCNA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4D2G, 1AXC, 1U76, 1U7B, 1UL1, 1VYJ, 1VYM, 1W60, 2ZVK, 2ZVL, 2ZVM, 3P87, 3TBL, 3VKX, 3WGW, 4RJF, 3JA9, 4ZTD, 5IY4, 5E0U, 5E0T, 5E0V
Identifiers
Aliases	PCNA, ATLD2, proliferating cell nuclear antigen
External IDs	OMIM: 176740 MGI: 97503 HomoloGene: 1945 GeneCards: PCNA
Gene location (Human) Chr. Chromosome 20 (human)^[1] Band 20p12.3 Start 5,114,953 bp^[1] End 5,126,626 bp^[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)^[2] Band 2 F2|2 64.15 cM Start 132,091,082 bp^[2] End 132,095,234 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in oocyte secondary oocyte ganglionic eminence cancellous bone rectum appendix bone marrow cavity of mouth sperm retinal pigment epithelium Top expressed in thymus yolk sac bone marrow secondary oocyte ileum spleen ovary stomach uterus placenta More reference expression data BioGPS More reference expression data
Gene ontology Molecular function MutLalpha complex binding identical protein binding enzyme binding receptor tyrosine kinase binding DNA binding DNA polymerase binding damaged DNA binding dinucleotide insertion or deletion binding protein binding chromatin binding histone acetyltransferase binding estrogen receptor binding purine-specific mismatch base pair DNA N-glycosylase activity DNA polymerase processivity factor activity Cellular component nucleus replisome nucleoplasm extracellular exosome DNA replication factor C complex centrosome PCNA complex nuclear replication fork PCNA-p21 complex replication fork nuclear body chromatin Biological process replication fork processing translesion synthesis DNA replication nucleotide-excision repair, DNA gap filling protein sumoylation regulation of DNA replication transcription-coupled nucleotide-excision repair positive regulation of deoxyribonuclease activity nucleotide-excision repair, DNA incision error-free translesion synthesis positive regulation of DNA repair regulation of transcription involved in G1/S transition of mitotic cell cycle positive regulation of DNA replication response to lipid heart development DNA mismatch repair cellular response to DNA damage stimulus mitotic telomere maintenance via semi-conservative replication epithelial cell differentiation response to cadmium ion cell population proliferation telomere maintenance error-prone translesion synthesis cellular response to UV estrous cycle cellular response to hydrogen peroxide response to dexamethasone nucleotide-excision repair, DNA incision, 5'-to lesion liver regeneration response to estradiol response to oxidative stress DNA repair response to L-glutamate DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest DNA ligation leading strand elongation protein ubiquitination telomere maintenance via semi-conservative replication viral process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5111 18538 Ensembl ENSG00000132646 ENSMUSG00000027342 UniProt P12004 P17918 RefSeq (mRNA) NM_182649 NM_002592 NM_011045 RefSeq (protein) NP_002583 NP_872590 NP_035175 Location (UCSC) Chr 20: 5.11 – 5.13 Mb Chr 2: 132.09 – 132.1 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

Cryo-EM structure of the DNA-bound PolD–PCNA processive complex

Many proteins interact with PCNA via the two known PCNA-interacting motifs PCNA-interacting peptide (PIP) box^[6] and AlkB homologue 2 PCNA interacting motif (APIM).^[7] 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.^[8]

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.^[9]

PCNA is also found in archaea, as a processivity factor of polD, the single multi-functional DNA polymerase in this domain of life.^[10]

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.^[11] Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone.^[12] PCNA helps hold DNA polymerase delta (Pol δ) to DNA. PCNA is clamped^[13] to DNA through the action of replication factor C (RFC),^[14] which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2F transcription factor-containing complexes.^[15][16]

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.^[17][18]

PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair (PRR).^[19] In PRR, there are two sub-pathways: (1) a translesion synthesis 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.^[20] 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^[20] 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.^[20] This antagonistic effect occurs because sumoylated PCNA recruits a DNA helicase called Srs2,^[21] which has a role in disrupting Rad51 nucleoprotein filaments fundamental for initiation of homologous recombination.

PCNA-binding proteins

PCNA interacts with many proteins.^[22]

• Apoptotic factors
• ATPases
• Base excision repair enzymes
• Cell-cycle regulators
• Chromatin remodeling factor
• Clamp loader
• Cohesin
• DNA ligase
• DNA methyltransferase
• DNA polymerases
• E2 SUMO-conjugating enzyme
• E3 ubiquitin ligases
• Flap endonuclease
• Helicases
• Histone acetyltransferase
• Histone chaperone
• Histone deacetylase
• Mismatch repair enzymes
• Licensing factor
• NKp44 receptor
• Nucleotide excision repair enzyme
• Poly ADP ribose polymerase
• Procaspases^[23]
• Protein kinases
• TCP protein domain
• Topoisomerase

Interactions

PCNA has been shown to interact with:

• Annexin A2^[24]
• CAF-1^[25][26][27]
• CDC25C^[28]
• CHTF18^[24]
• Cyclin D1^[29][30]
• Cyclin O^[24][31]
• Cyclin-dependent kinase 4^[30][32]
• Cyclin-dependent kinase inhibitor 1C^[33]
• DNMT1^[34][35][36]
• EP300^[37]
• Establishment of Sister Chromatid Cohesion 2^[38]
• Flap structure-specific endonuclease 1^{[39][40][41][42][43][44][45]}
• GADD45A^{[46][47][48][49][50]}
• GADD45G^[51][52]
• HDAC1^[53]
• HUS1^[54]
• ING1^[55]
• KCTD13^[56]
• KIAA0101^[45]
• Ku70^[24][57]
• Ku80^[24][57][58]
• MCL1^[59]
• MSH3^[24][60][61]
• MSH6^[24][60][61]
• MUTYH^[62]
• P21^{[33][41][45][63][64][65][66][67]}
• POLD2^[68]
• POLD3^[24][69]
• POLDIP2^[70]
• POLH^[71]
• POLL^[72][73][74]
• RFC1^{[24][63][75][76][77]}
• RFC2^[24][78][79]
• RFC3^[24][80]
• RFC4^[24][78]
• RFC5^[24][76][78]
• Ubiquitin C^[81][82][83]
• Werner syndrome ATP-dependent helicase^[84][85]
• XRCC1^[86]
• Y box binding protein 1^[87]

Proteins interacting with PCNA via APIM include human AlkB homologue 2, TFIIS-L, TFII-I, Rad51B,^[7] XPA,^[88] ZRANB3,^[89] and FBH1.^[90]

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.^[91] 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 by 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 they can be used in situ in living tissue and even distinguish cells undergoing replication from cells undergoing repair.^[92]

caPCNA, a post-translationally modified isoform of PCNA common in cancer cells, is a potential therapeutic target in cancer therapy.^[93][94] In 2023 City of Hope National Medical Center published preclinical research on a targeted chemotherapy using AOH1996 that appears to suppress tumor growth without causing discernable side effects.^[95]

See also

• Ki-67 – cellular marker for proliferation
• Transcription

References

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Further reading

• Almendral JM, Huebsch D, Blundell PA, Macdonald-Bravo H, Bravo R (March 1987). "Cloning and sequence of the human nuclear protein cyclin: homology with DNA-binding proteins". Proceedings of the National Academy of Sciences of the United States of America. 84 (6): 1575–1579. Bibcode:1987PNAS...84.1575A. doi:10.1073/pnas.84.6.1575. PMC 304478. PMID 2882507.
• Chen IT, Smith ML, O'Connor PM, Fornace AJ (November 1995). "Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA". Oncogene. 11 (10): 1931–1937. PMID 7478510.
• Chen M, Pan ZQ, Hurwitz J (April 1992). "Sequence and expression in Escherichia coli of the 40-kDa subunit of activator 1 (replication factor C) of HeLa cells". Proceedings of the National Academy of Sciences of the United States of America. 89 (7): 2516–2520. Bibcode:1992PNAS...89.2516C. doi:10.1073/pnas.89.7.2516. PMC 48692. PMID 1313560.
• Fukuda K, Morioka H, Imajou S, Ikeda S, Ohtsuka E, Tsurimoto T (September 1995). "Structure-function relationship of the eukaryotic DNA replication factor, proliferating cell nuclear antigen". The Journal of Biological Chemistry. 270 (38): 22527–22534. doi:10.1074/jbc.270.38.22527. PMID 7673244.
• Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E, Cox LS (June 1995). "Characterisation of the interaction between PCNA and Gadd45". Oncogene. 10 (12): 2427–2433. PMID 7784094.
• Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N, et al. (December 1994). "Construction of a human full-length cDNA bank". Gene. 150 (2): 243–250. doi:10.1016/0378-1119(94)90433-2. PMID 7821789.
• Kemeny MM, Alava G, Oliver JM (November 1992). "Improving responses in hepatomas with circadian-patterned hepatic artery infusions of recombinant interleukin-2". Journal of Immunotherapy. 12 (4): 219–223. doi:10.1097/00002371-199211000-00001. PMID 1477073.
• Krotz D (28 July 2004). . ALSNews. Vol. 243. Lawrence Berkeley National Laboratory. Archived from the original on 11 October 2004. Retrieved 3 August 2023.
• Ku DH, Travali S, Calabretta B, Huebner K, Baserga R (July 1989). "Human gene for proliferating cell nuclear antigen has pseudogenes and localizes to chromosome 20". Somatic Cell and Molecular Genetics. 15 (4): 297–307. doi:10.1007/BF01534969. PMID 2569765. S2CID 27217843.
• Li X, Li J, Harrington J, Lieber MR, Burgers PM (September 1995). "Lagging strand DNA synthesis at the eukaryotic replication fork involves binding and stimulation of FEN-1 by proliferating cell nuclear antigen". The Journal of Biological Chemistry. 270 (38): 22109–22112. doi:10.1074/jbc.270.38.22109. PMID 7673186.
• Matsuoka S, Yamaguchi M, Matsukage A (April 1994). "D-type cyclin-binding regions of proliferating cell nuclear antigen". The Journal of Biological Chemistry. 269 (15): 11030–11036. doi:10.1016/S0021-9258(19)78087-9. PMID 7908906.
• Miura M (March 1999). "Detection of chromatin-bound PCNA in mammalian cells and its use to study DNA excision repair". Journal of Radiation Research. 40 (1): 1–12. Bibcode:1999JRadR..40....1M. doi:10.1269/jrr.40.1. PMID 10408173.
• Miyata T, Suzuki H, Oyama T, Mayanagi K, Ishino Y, Morikawa K (September 2005). "Open clamp structure in the clamp-loading complex visualized by electron microscopic image analysis". Proceedings of the National Academy of Sciences of the United States of America. 102 (39): 13795–13800. Bibcode:2005PNAS..10213795M. doi:10.1073/pnas.0506447102. PMC 1236569. PMID 16169902.
• Morris GF, Mathews MB (September 1990). "Analysis of the proliferating cell nuclear antigen promoter and its response to adenovirus early region 1". The Journal of Biological Chemistry. 265 (27): 16116–16125. doi:10.1016/S0021-9258(17)46196-5. PMID 1975809.
• 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". Proceedings of the National Academy of Sciences of the United States of America. 90 (1): 6–10. Bibcode:1993PNAS...90....6P. doi:10.1073/pnas.90.1.6. PMC 45588. PMID 8093561.
• 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): 471–475. Bibcode:1987Natur.326..471P. doi:10.1038/326471a0. PMID 2882422. S2CID 4336365.
• Prosperi E (1998). "Multiple roles of the proliferating cell nuclear antigen: DNA replication, repair and cell cycle control". Progress in Cell Cycle Research. Vol. 3. pp. 193–210. doi:10.1007/978-1-4615-5371-7_15. ISBN 978-1-4613-7451-0. PMID 9552415.
• Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, et al. (November 1994). "Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen". Science (Submitted manuscript). 266 (5189): 1376–1380. Bibcode:1994Sci...266.1376S. doi:10.1126/science.7973727. PMID 7973727.
• Szepesi A, Gelfand EW, Lucas JJ (November 1994). "Association of proliferating cell nuclear antigen with cyclin-dependent kinases and cyclins in normal and transformed human T lymphocytes". Blood. 84 (10): 3413–3421. doi:10.1182/blood.V84.10.3413.3413. PMID 7949095.
• Travali S, Ku DH, Rizzo MG, Ottavio L, Baserga R, Calabretta B (May 1989). "Structure of the human gene for the proliferating cell nuclear antigen". The Journal of Biological Chemistry. 264 (13): 7466–7472. doi:10.1016/S0021-9258(18)83257-4. hdl:11380/811513. PMID 2565339.
• Warbrick E, Lane DP, Glover DM, Cox LS (March 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". Current Biology. 5 (3): 275–282. doi:10.1016/S0960-9822(95)00058-3. PMID 7780738. S2CID 1559243.
• Webb G, Parsons P, Chenevix-Trench G (November 1990). "Localization of the gene for human proliferating nuclear antigen/cyclin by in situ hybridization". Human Genetics. 86 (1): 84–86. doi:10.1007/bf00205180. PMID 1979311. S2CID 27107553.

External links

• PCNA at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• —Antibody Patterns.com
• Overview of all the structural information available in the PDB for UniProt: P12004 (Proliferating cell nuclear antigen) at the PDBe-KB.