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.[4]
![](../I/m/page1-220px-Cryo-EM_structure_of_the_DNA-bound_PolD%E2%80%93PCNA_processive_complex.pdf.jpg)
Many proteins interact with PCNA via the two known PCNA-interacting motifs PCNA-interacting peptide (PIP) box[5] and AlkB homologue 2 PCNA interacting motif (APIM).[6] 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.[7]
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.[8]
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.[9] Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone.[10] PCNA helps hold DNA polymerase epsilon (Pol ε) to DNA. PCNA is clamped[11] to DNA through the action of replication factor C (RFC),[12] which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2F transcription factor-containing complexes.[13] [14]
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.[15][16]
PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair (PRR).[17] 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.[18] 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[18] 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.[18] This antagonistic effect occurs because sumoylated PCNA recruits a DNA helicase called Srs2,[19] which has a role in disrupting Rad51 nucleoprotein filaments fundamental for initiation of homologous recombination.
PCNA-binding proteins
PCNA interacts with many proteins.[20]
- 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
- NKp44 receptor
- Nucleotide excision repair enzyme
- Poly ADP ribose polymerase
- Procaspases[21]
- Protein kinases
- Licensing factor
- TCP protein domain
- Topoisomerase
Interactions
PCNA has been shown to interact with:
- Annexin A2,[22]
- CAF-1,[23][24][25]
- CDC25C,[26]
- CHTF18,[22]
- Cyclin D1,[27][28]
- Cyclin O,[22][29]
- Cyclin-dependent kinase 4,[28][30]
- Cyclin-dependent kinase inhibitor 1C,[31]
- DNMT1,[32][33][34]
- EP300,[35]
- Establishment of Sister Chromatid Cohesion 2,[36]
- Flap structure-specific endonuclease 1,[37][38][39][40][41][42][43]
- GADD45A,[44][45][46][47][48]
- GADD45G,[49][50]
- HDAC1,[51]
- HUS1,[52]
- ING1,[53]
- KCTD13,[54]
- KIAA0101,[43]
- Ku70,[22][55]
- Ku80,[22][55][56]
- MCL1,[57]
- MSH3,[22][58][59]
- MSH6,[22][58][59]
- MUTYH,[60]
- P21,[31][39][43][61][62][63][64][65]
- POLD2,[66]
- POLD3,[22][67]
- POLDIP2,[68]
- POLH,[69]
- POLL,[70][71][72]
- RFC1,[22][61][73][74][75]
- RFC2,[22][76][77]
- RFC3,[22][78]
- RFC4,[22][76]
- RFC5,[22][74][76]
- Ubiquitin C[79][80][81]
- Werner syndrome ATP-dependent helicase,[82][83]
- XRCC1,[84] and
- Y box binding protein 1.[85]
Proteins interacting with PCNA via APIM include human AlkB homologue 2, TFIIS-L, TFII-I, Rad51B,[6] XPA,[86] ZRANB3,[87] and FBH1.[88]
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.[89] 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.[90]
PCNA is a potential therapeutic target in cancer therapy.[91]
See also
- Ki-67 – cellular marker for proliferation
- Transcription
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- 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.
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- 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.
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- Cai J, Gibbs E, Uhlmann F, Phillips B, Yao N, O'Donnell M, Hurwitz J (July 1997). "A complex consisting of human replication factor C p40, p37, and p36 subunits is a DNA-dependent ATPase and an intermediate in the assembly of the holoenzyme". J. Biol. Chem. 272 (30): 18974–81. doi:10.1074/jbc.272.30.18974. PMID 9228079.
- 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.
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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. pp. 193–210. doi:10.1007/978-1-4615-5371-7_15. ISBN 978-1-4613-7451-0. 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. doi:10.1182/blood.V84.10.3413.3413. 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 (Submitted manuscript). 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.
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.
- "Movie showing a model of clamp loading of PCNA onto DNA". Pubmed Central.
- Overview of all the structural information available in the PDB for UniProt: P12004 (Proliferating cell nuclear antigen) at the PDBe-KB.