Proliferating cell nuclear antigen explained

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]

PCNA is also found in archaea, as a processivity factor of polD, the single multi-functional DNA polymerase in this domain of life.^[6]

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.^[7] Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone.^[8] PCNA helps hold DNA polymerase delta (Pol δ) to DNA. PCNA is clamped^[9] to DNA through the action of replication factor C (RFC),^[10] which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2F transcription factor-containing complexes.^{[11] [12]}

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.^{[13] [14]}

PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair (PRR).^[15] 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.^[16] 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 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. This antagonistic effect occurs because sumoylated PCNA recruits a DNA helicase called Srs2,^[17] which has a role in disrupting Rad51 nucleoprotein filaments fundamental for initiation of homologous recombination.

PCNA-binding proteins

PCNA interacts with many proteins.^[18]

• 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^[19]
• Protein kinases
• TCP protein domain
• Topoisomerase

Interactions

PCNA has been shown to interact with:

• Annexin A2
• CAF-1^{[20] [21] [22]}
• CDC25C^[23]
• CHTF18
• Cyclin D1^{[24] [25]}
• Cyclin O^[26]
• Cyclin-dependent kinase 4^[27]
• Cyclin-dependent kinase inhibitor 1C^[28]
• DNMT1^{[29] [30] [31]}
• EP300^[32]
• Establishment of Sister Chromatid Cohesion 2^[33]
• Flap structure-specific endonuclease 1^{[34] [35] [36] [37] [38] [39] [40]}
• GADD45A^{[41] [42] [43] [44] [45]}
• GADD45G^{[46] [47]}
• HDAC1^[48]
• HUS1^[49]
• ING1^[50]
• KCTD13^[51]
• KIAA0101
• Ku70^{[52] [53]}
• Ku80^[54]
• MCL1^[55]
• MSH3^{[56] [57]}
• MSH6
• MUTYH^[58]
• P21^{[59] [60] [61] [62]}
• POLD2^[63]
• POLD3^[64]
• POLDIP2^[65]
• POLH^[66]
• POLL^{[67] [68] [69]}
• RFC1^{[70] [71] [72] [73]}
• RFC2^{[74] [75]}
• RFC3^[76]
• RFC4
• RFC5
• Ubiquitin C^{[77] [78] [79]}
• Werner syndrome ATP-dependent helicase^{[80] [81]}
• XRCC1^[82]
• Y box binding protein 1^[83]

Proteins interacting with PCNA via APIM include human AlkB homologue 2, TFIIS-L, TFII-I, Rad51B, XPA,^[84] ZRANB3,^[85] and FBH1.^[86]

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.^[87] 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.^[88]

caPCNA, a post-translationally modified isoform of PCNA common in cancer cells, is a potential therapeutic target in cancer therapy.^{[89] [90]} 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.^[91]

See also

• Ki-67 – cellular marker for proliferation
• Transcription

Further reading

• Almendral JM, Huebsch D, Blundell PA, Macdonald-Bravo H, Bravo R . 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 . March 1987 . 2882507 . 304478 . 10.1073/pnas.84.6.1575 . free . 1987PNAS...84.1575A .
• Chen IT, Smith ML, O'Connor PM, Fornace AJ . Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA . Oncogene . 11 . 10 . 1931–1937 . November 1995 . 7478510 .
• Chen M, Pan ZQ, Hurwitz J . 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 . April 1992 . 1313560 . 48692 . 10.1073/pnas.89.7.2516 . free . 1992PNAS...89.2516C .
• Fukuda K, Morioka H, Imajou S, Ikeda S, Ohtsuka E, Tsurimoto T . Structure-function relationship of the eukaryotic DNA replication factor, proliferating cell nuclear antigen . The Journal of Biological Chemistry . 270 . 38 . 22527–22534 . September 1995 . 7673244 . 10.1074/jbc.270.38.22527 . free .
• Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E, Cox LS . Characterisation of the interaction between PCNA and Gadd45 . Oncogene . 10 . 12 . 2427–2433 . June 1995 . 7784094 .
• Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N, Yokoyama-Kobayashi M, Aoki T . 6 . Construction of a human full-length cDNA bank . Gene . 150 . 2 . 243–250 . December 1994 . 7821789 . 10.1016/0378-1119(94)90433-2 .
• Kemeny MM, Alava G, Oliver JM . Improving responses in hepatomas with circadian-patterned hepatic artery infusions of recombinant interleukin-2 . Journal of Immunotherapy . 12 . 4 . 219–223 . November 1992 . 1477073 . 10.1097/00002371-199211000-00001 .
• News: Krotz D . 28 July 2004 . Structure of a clamp–loader complex . https://web.archive.org/web/20041011094740/http://www-als.lbl.gov/als/science/sci_archive/80slidingclamp.html . 11 October 2004 . . . 243 . 3 August 2023.
• Ku DH, Travali S, Calabretta B, Huebner K, Baserga R . Human gene for proliferating cell nuclear antigen has pseudogenes and localizes to chromosome 20 . Somatic Cell and Molecular Genetics . 15 . 4 . 297–307 . July 1989 . 2569765 . 10.1007/BF01534969 . 27217843 .
• Li X, Li J, Harrington J, Lieber MR, Burgers PM . 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 . September 1995 . 7673186 . 10.1074/jbc.270.38.22109 . free .
• Matsuoka S, Yamaguchi M, Matsukage A . D-type cyclin-binding regions of proliferating cell nuclear antigen . The Journal of Biological Chemistry . 269 . 15 . 11030–11036 . April 1994 . 7908906 . 10.1016/S0021-9258(19)78087-9 . free .
• Miura M . Detection of chromatin-bound PCNA in mammalian cells and its use to study DNA excision repair . Journal of Radiation Research . 40 . 1 . 1–12 . March 1999 . 10408173 . 10.1269/jrr.40.1 . free . 1999JRadR..40....1M .
• Miyata T, Suzuki H, Oyama T, Mayanagi K, Ishino Y, Morikawa K . 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 . September 2005 . 16169902 . 1236569 . 10.1073/pnas.0506447102 . 2005PNAS..10213795M . free .
• Morris GF, Mathews MB . 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 . September 1990 . 1975809 . 10.1016/S0021-9258(17)46196-5 . free .
• Pan ZQ, Chen M, Hurwitz J . 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 . January 1993 . 8093561 . 45588 . 10.1073/pnas.90.1.6 . free . 1993PNAS...90....6P .
• Prelich G, Kostura M, Marshak DR, Mathews MB, Stillman B . The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro . Nature . 326 . 6112 . 471–475 . 1987 . 2882422 . 10.1038/326471a0 . 4336365 . 1987Natur.326..471P .
• Book: Prosperi E . Multiple roles of the proliferating cell nuclear antigen: DNA replication, repair and cell cycle control . Progress in Cell Cycle Research . 3 . 193–210 . 1998 . 9552415 . 10.1007/978-1-4615-5371-7_15 . 978-1-4613-7451-0 .
• Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ . 6 . Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen . Science . 266 . 5189 . 1376–1380 . November 1994 . 7973727 . 10.1126/science.7973727 . Submitted manuscript . 1994Sci...266.1376S .
• Szepesi A, Gelfand EW, Lucas JJ . Association of proliferating cell nuclear antigen with cyclin-dependent kinases and cyclins in normal and transformed human T lymphocytes . Blood . 84 . 10 . 3413–3421 . November 1994 . 7949095 . 10.1182/blood.V84.10.3413.3413 . free .
• Travali S, Ku DH, Rizzo MG, Ottavio L, Baserga R, Calabretta B . Structure of the human gene for the proliferating cell nuclear antigen . The Journal of Biological Chemistry . 264 . 13 . 7466–7472 . May 1989 . 2565339 . 10.1016/S0021-9258(18)83257-4 . free . 11380/811513 . free .
• Warbrick E, Lane DP, Glover DM, Cox LS . 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 . March 1995 . 7780738 . 10.1016/S0960-9822(95)00058-3 . 1559243 . free .
• Webb G, Parsons P, Chenevix-Trench G . Localization of the gene for human proliferating nuclear antigen/cyclin by in situ hybridization . Human Genetics . 86 . 1 . 84–86 . November 1990 . 1979311 . 10.1007/bf00205180 . 27107553 .

External links

• • ANA: Cell cycle related (Mitotic): PCNA type 1 and type 2 Antibody Patterns—Antibody Patterns.com

Notes and References

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