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.[1]
PCNA was originally identified as an antigen that is expressed in the nuclei of cells during the DNA synthesis phase of the cell cycle.[2] Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone.[3] PCNA helps hold DNA polymerase delta (Pol δ) to DNA. PCNA is clamped[4] to DNA through the action of replication factor C (RFC),[5] which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2Ftranscription factor-containing complexes.[6]
Role in DNA repair
Since DNA polymerase delta is involved in resynthesis of excised damaged DNA strands during DNA repair, PCNA is important for both DNA synthesis and DNA repair.[7] PCNA is also involved in the switch to DNA damage bypass translesion synthesis.
^ Leonardi E, Girlando S, Serio G, Mauri FA, Perrone G, Scampini S, Dalla Palma P, Barbareschi M (1992). "PCNA and Ki67 expression in breast carcinoma: correlations with clinical and biological variables". J. Clin. Pathol.45 (5): 416–9. doi:10.1136/jcp.45.5.416. PMID 1350788.
^ ab Bowman GD, O'Donnell M, Kuriyan J (2004). "Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex". Nature429 (6993): 724–30. doi:10.1038/nature02585. PMID 15201901.
^ Zhang G, Gibbs E, Kelman Z, O'Donnell M, Hurwitz J (1999). "Studies on the interactions between human replication factor C and human proliferating cell nuclear antigen". Proc. Natl. Acad. Sci. U.S.A.96 (5): 1869–74. doi:10.1073/pnas.96.5.1869. PMID 10051561.
^ Egelkrout EM, Mariconti L, Settlage SB, Cella R, Robertson D, Hanley-Bowdoin L (2002). "Two E2F elements regulate the proliferating cell nuclear antigen promoter differently during leaf development". Plant Cell14 (12): 3225–36. doi:10.1105/tpc.006403. PMID 12468739.
^ Essers J, Theil AF, Baldeyron C, van Cappellen WA, Houtsmuller AB, Kanaar R, Vermeulen W (2005). "Nuclear dynamics of PCNA in DNA replication and repair". Mol. Cell. Biol.25 (21): 9350–9. doi:10.1128/MCB.25.21.9350-9359.2005. PMID 16227586.
^ Miyata T, Suzuki H, Oyama T, Mayanagi K, Ishino Y, Morikawa K (2005). "Open clamp structure in the clamp-loading complex visualized by electron microscopic image analysis". Proc. Natl. Acad. Sci. U.S.A.102 (39): 13795–800. doi:10.1073/pnas.0506447102. PMID 16169902.
Further reading
Prosperi E (1998). "Multiple roles of the proliferating cell nuclear antigen: DNA replication, repair and cell cycle control.". Progress in cell cycle research3: 193–210. 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. 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): 2516–20. 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): 219–23. 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. PMID 1979311.
Travali S, Ku DH, Rizzo MG, et al. (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, et al. (1989). "Human gene for proliferating cell nuclear antigen has pseudogenes and localizes to chromosome 20.". Somat. Cell Mol. Genet.15 (4): 297–307. PMID 2569765.
Prelich G, Kostura M, Marshak DR, et al. (1987). "The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro.". Nature326 (6112): 471–5. doi:10.1038/326471a0. PMID 2882422.
Almendral JM, Huebsch D, Blundell PA, et al. (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. 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.". Oncogene11 (10): 1931–7. PMID 7478510.
Li X, Li J, Harrington J, et al. (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. PMID 7673186.
Fukuda K, Morioka H, Imajou S, et al. (1995). "Structure-function relationship of the eukaryotic DNA replication factor, proliferating cell nuclear antigen.". J. Biol. Chem.270 (38): 22527–34. 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): 275–82. PMID 7780738.
Hall PA, Kearsey JM, Coates PJ, et al. (1995). "Characterisation of the interaction between PCNA and Gadd45.". Oncogene10 (12): 2427–33. PMID 7784094.
Kato S, Sekine S, Oh SW, et al. (1995). "Construction of a human full-length cDNA bank.". Gene150 (2): 243–50. 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.". Blood84 (10): 3413–21. PMID 7949095.
Smith ML, Chen IT, Zhan Q, et al. (1994). "Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen.". Science266 (5189): 1376–80. 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. PMID 8093561.