proliferating cell nuclear antigen

File:Cryo-EM structure of the DNA-bound PolD–PCNA processive complex.pdf

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.

Many proteins interact with PCNA via the two known PCNA-interacting motifs PCNA-interacting peptide (PIP) box{{cite journal | vauthors = Warbrick E | title = PCNA binding through a conserved motif | journal = BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology | volume = 20 | issue = 3 | pages = 195–199 | date = March 1998 | pmid = 9631646 | doi = 10.1002/(sici)1521-1878(199803)20:3<195::aid-bies2>3.0.co;2-r }} and AlkB homologue 2 PCNA interacting motif (APIM).{{cite journal | vauthors = Gilljam KM, Feyzi E, Aas PA, Sousa MM, Müller R, Vågbø CB, Catterall TC, Liabakk NB, Slupphaug G, Drabløs F, Krokan HE, Otterlei M | title = Identification of a novel, widespread, and functionally important PCNA-binding motif | journal = The Journal of Cell Biology | volume = 186 | issue = 5 | pages = 645–654 | date = September 2009 | pmid = 19736315 | pmc = 2742182 | doi = 10.1083/jcb.200903138 }} 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.{{cite journal | vauthors = Mailand N, Gibbs-Seymour I, Bekker-Jensen S | title = Regulation of PCNA-protein interactions for genome stability | journal = Nature Reviews. Molecular Cell Biology | volume = 14 | issue = 5 | pages = 269–282 | date = May 2013 | pmid = 23594953 | doi = 10.1038/nrm3562 | s2cid = 25952152 }}

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.{{Cite web | title = Entrez Gene: PCNA proliferating cell nuclear antigen | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5111 }}

PCNA is also ubiquitous in archaea, where it typically serves as a processivity factor for the replicative polymerases, particularly for polD.{{Cite journal | vauthors = Madru C, Henneke G, Raia P, Hugonneau-Beaufet I, Pehau-Arnaudet G, England P, Lindahl E, Delarue M, Carroni M, Sauguet L | title = Structural basis for the increased processivity of D-family DNA polymerases in complex with PCNA | journal = Nature Communications | volume = 11 | issue = 1 | pages = 1591 | date = 2020-03-27 | pmid = 32221299 | pmc = 7101311 | doi = 10.1038/s41467-020-15392-9 | bibcode = 2020NatCo..11.1591M | language = en | issn = 2041-1723 }} However, in the Sulfolobus genus, it also functions as a processivity factor for the replicative polB polymerase.{{Cite journal | vauthors = Yan J, Beattie TR, Rojas AL, Schermerhorn K, Gristwood T, Trinidad JC, Albers SV, Roversi P, Gardner AF, Abrescia NG, Bell SD | title = Identification and characterization of a heterotrimeric archaeal DNA polymerase holoenzyme | journal = Nature Communications | volume = 8 | issue = 1 | pages = 15075 | date = 2017-05-02 | pmid = 28462924 | doi = 10.1038/ncomms15075 | pmc = 5418573 | bibcode = 2017NatCo...815075Y | language = en | issn = 2041-1723 | hdl = 2381/43088 | hdl-access = free }}

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.{{cite journal | vauthors = Leonardi E, Girlando S, Serio G, Mauri FA, Perrone G, Scampini S, Dalla Palma P, Barbareschi M | title = PCNA and Ki67 expression in breast carcinoma: correlations with clinical and biological variables | journal = Journal of Clinical Pathology | volume = 45 | issue = 5 | pages = 416–419 | date = May 1992 | pmid = 1350788 | pmc = 495304 | doi = 10.1136/jcp.45.5.416 }} Part of the protein was sequenced and that sequence was used to allow isolation of a cDNA clone.{{cite journal | vauthors = Matsumoto K, Moriuchi T, Koji T, Nakane PK | title = Molecular cloning of cDNA coding for rat proliferating cell nuclear antigen (PCNA)/cyclin | journal = The EMBO Journal | volume = 6 | issue = 3 | pages = 637–642 | date = March 1987 | pmid = 2884104 | pmc = 553445 | doi = 10.1002/j.1460-2075.1987.tb04802.x }} PCNA helps hold DNA polymerase delta (Pol δ) to DNA. PCNA is clamped{{cite journal | vauthors = Bowman GD, O'Donnell M, Kuriyan J | title = Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex | journal = Nature | volume = 429 | issue = 6993 | pages = 724–730 | date = June 2004 | pmid = 15201901 | doi = 10.1038/nature02585 | s2cid = 4346799 | bibcode = 2004Natur.429..724B }} to DNA through the action of replication factor C (RFC),{{cite journal | vauthors = Zhang G, Gibbs E, Kelman Z, O'Donnell M, Hurwitz J | title = Studies on the interactions between human replication factor C and human proliferating cell nuclear antigen | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 5 | pages = 1869–1874 | date = March 1999 | pmid = 10051561 | pmc = 26703 | doi = 10.1073/pnas.96.5.1869 | doi-access = free | bibcode = 1999PNAS...96.1869Z }} which is a heteropentameric member of the AAA+ class of ATPases. Expression of PCNA is under the control of E2F transcription factor-containing complexes.{{cite journal | vauthors = Egelkrout EM, Mariconti L, Settlage SB, Cella R, Robertson D, Hanley-Bowdoin L | title = Two E2F elements regulate the proliferating cell nuclear antigen promoter differently during leaf development | journal = The Plant Cell | volume = 14 | issue = 12 | pages = 3225–3236 | date = December 2002 | pmid = 12468739 | pmc = 151214 | doi = 10.1105/tpc.006403 | bibcode = 2002PlanC..14.3225E }}

{{cite journal | vauthors = Nikolai BC, Lanz RB, York B, Dasgupta S, Mitsiades N, Creighton CJ, Tsimelzon A, Hilsenbeck SG, Lonard DM, Smith CL, O'Malley BW | title = HER2 Signaling Drives DNA Anabolism and Proliferation through SRC-3 Phosphorylation and E2F1-Regulated Genes | journal = Cancer Research | volume = 76 | issue = 6 | pages = 1463–1475 | date = March 2016 | pmid = 26833126 | pmc = 4794399 | doi = 10.1158/0008-5472.CAN-15-2383 }}

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.{{cite journal | vauthors = Shivji KK, Kenny MK, Wood RD | title = Proliferating cell nuclear antigen is required for DNA excision repair | journal = Cell | volume = 69 | issue = 2 | pages = 367–374 | date = April 1992 | pmid = 1348971 | doi = 10.1016/0092-8674(92)90416-A | s2cid = 12260457 }}{{cite journal | vauthors = Essers J, Theil AF, Baldeyron C, van Cappellen WA, Houtsmuller AB, Kanaar R, Vermeulen W | title = Nuclear dynamics of PCNA in DNA replication and repair | journal = Molecular and Cellular Biology | volume = 25 | issue = 21 | pages = 9350–9359 | date = November 2005 | pmid = 16227586 | pmc = 1265825 | doi = 10.1128/MCB.25.21.9350-9359.2005 }}

PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair (PRR).{{cite journal | vauthors = Lehmann AR, Fuchs RP | title = Gaps and forks in DNA replication: Rediscovering old models | journal = DNA Repair | volume = 5 | issue = 12 | pages = 1495–1498 | date = December 2006 | pmid = 16956796 | doi = 10.1016/j.dnarep.2006.07.002 | url = http://sro.sussex.ac.uk/id/eprint/545/1/Gaps_and_forks3-07.pdf }} 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.{{cite journal | vauthors = Hoege C, Pfander B, Moldovan GL, Pyrowolakis G, Jentsch S | title = RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO | journal = Nature | volume = 419 | issue = 6903 | pages = 135–141 | date = September 2002 | pmid = 12226657 | doi = 10.1038/nature00991 | s2cid = 205209495 | bibcode = 2002Natur.419..135H }} 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,{{cite journal | vauthors = Pfander B, Moldovan GL, Sacher M, Hoege C, Jentsch S | title = SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase | journal = Nature | volume = 436 | issue = 7049 | pages = 428–433 | date = July 2005 | pmid = 15931174 | doi = 10.1038/nature03665 | s2cid = 4316517 | bibcode = 2005Natur.436..428P }} which has a role in disrupting Rad51 nucleoprotein filaments fundamental for initiation of homologous recombination.

PCNA-binding proteins

PCNA interacts with many proteins.{{cite journal | vauthors = Moldovan GL, Pfander B, Jentsch S | title = PCNA, the maestro of the replication fork | journal = Cell | volume = 129 | issue = 4 | pages = 665–679 | date = May 2007 | pmid = 17512402 | doi = 10.1016/j.cell.2007.05.003 | s2cid = 3547069 | doi-access = free }}

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{{cite journal | vauthors = Witko-Sarsat V, Mocek J, Bouayad D, Tamassia N, Ribeil JA, Candalh C, Davezac N, Reuter N, Mouthon L, Hermine O, Pederzoli-Ribeil M, Cassatella MA | title = Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival | journal = The Journal of Experimental Medicine | volume = 207 | issue = 12 | pages = 2631–2645 | date = November 2010 | pmid = 20975039 | pmc = 2989777 | doi = 10.1084/jem.20092241 }}
Protein kinases
TCP protein domain
Topoisomerase

Interactions

PCNA has been shown to interact with:

Annexin A2
CAF-1{{cite journal | vauthors = Zhang K, Gao Y, Li J, Burgess R, Han J, Liang H, Zhang Z, Liu Y | title = A DNA binding winged helix domain in CAF-1 functions with PCNA to stabilize CAF-1 at replication forks | journal = Nucleic Acids Research | volume = 44 | issue = 11 | pages = 5083–5094 | date = June 2016 | pmid = 26908650 | pmc = 4914081 | doi = 10.1093/nar/gkw106 }}{{cite journal | vauthors = Moggs JG, Grandi P, Quivy JP, Jónsson ZO, Hübscher U, Becker PB, Almouzni G | title = A CAF-1-PCNA-mediated chromatin assembly pathway triggered by sensing DNA damage | journal = Molecular and Cellular Biology | volume = 20 | issue = 4 | pages = 1206–1218 | date = February 2000 | pmid = 10648606 | pmc = 85246 | doi = 10.1128/mcb.20.4.1206-1218.2000 }}{{cite journal | vauthors = Rolef Ben-Shahar T, Castillo AG, Osborne MJ, Borden KL, Kornblatt J, Verreault A | title = Two fundamentally distinct PCNA interaction peptides contribute to chromatin assembly factor 1 function | journal = Molecular and Cellular Biology | volume = 29 | issue = 24 | pages = 6353–6365 | date = December 2009 | pmid = 19822659 | pmc = 2786881 | doi = 10.1128/MCB.01051-09 }}
CDC25C{{cite journal | vauthors = Kawabe T, Suganuma M, Ando T, Kimura M, Hori H, Okamoto T | title = Cdc25C interacts with PCNA at G2/M transition | journal = Oncogene | volume = 21 | issue = 11 | pages = 1717–1726 | date = March 2002 | pmid = 11896603 | doi = 10.1038/sj.onc.1205229 | doi-access = free }}
CHTF18
Cyclin D1{{cite journal | vauthors = Matsuoka S, Yamaguchi M, Matsukage A | title = D-type cyclin-binding regions of proliferating cell nuclear antigen | journal = The Journal of Biological Chemistry | volume = 269 | issue = 15 | pages = 11030–11036 | date = April 1994 | pmid = 7908906 | doi = 10.1016/S0021-9258(19)78087-9 | doi-access = free }}{{cite journal | vauthors = Xiong Y, Zhang H, Beach D | title = Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation | journal = Genes & Development | volume = 7 | issue = 8 | pages = 1572–1583 | date = August 1993 | pmid = 8101826 | doi = 10.1101/gad.7.8.1572 | doi-access = free }}
Cyclin O{{cite journal | vauthors = Otterlei M, Warbrick E, Nagelhus TA, Haug T, Slupphaug G, Akbari M, Aas PA, Steinsbekk K, Bakke O, Krokan HE | title = Post-replicative base excision repair in replication foci | journal = The EMBO Journal | volume = 18 | issue = 13 | pages = 3834–3844 | date = July 1999 | pmid = 10393198 | pmc = 1171460 | doi = 10.1093/emboj/18.13.3834 }}
Cyclin-dependent kinase 4{{cite journal | vauthors = Serrano M, Hannon GJ, Beach D | title = A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 | journal = Nature | volume = 366 | issue = 6456 | pages = 704–707 | date = December 1993 | pmid = 8259215 | doi = 10.1038/366704a0 | s2cid = 4368128 | bibcode = 1993Natur.366..704S }}
Cyclin-dependent kinase inhibitor 1C{{cite journal | vauthors = Watanabe H, Pan ZQ, Schreiber-Agus N, DePinho RA, Hurwitz J, Xiong Y | title = Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 4 | pages = 1392–1397 | date = February 1998 | pmid = 9465025 | pmc = 19016 | doi = 10.1073/pnas.95.4.1392 | bibcode = 1998PNAS...95.1392W | doi-access = free }}
DNMT1{{cite journal | vauthors = Rountree MR, Bachman KE, Baylin SB | title = DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci | journal = Nature Genetics | volume = 25 | issue = 3 | pages = 269–277 | date = July 2000 | pmid = 10888872 | doi = 10.1038/77023 | s2cid = 26149386 }}{{cite journal | vauthors = Iida T, Suetake I, Tajima S, Morioka H, Ohta S, Obuse C, Tsurimoto T | title = PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA | journal = Genes to Cells | volume = 7 | issue = 10 | pages = 997–1007 | date = October 2002 | pmid = 12354094 | doi = 10.1046/j.1365-2443.2002.00584.x | s2cid = 25310911 | doi-access = free }}{{cite journal | vauthors = Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF | title = Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1 | journal = Science | location = New York, N.Y. | volume = 277 | issue = 5334 | pages = 1996–2000 | date = September 1997 | pmid = 9302295 | doi = 10.1126/science.277.5334.1996 }}
EP300{{cite journal | vauthors = Hasan S, Hassa PO, Imhof R, Hottiger MO | title = Transcription coactivator p300 binds PCNA and may have a role in DNA repair synthesis | journal = Nature | volume = 410 | issue = 6826 | pages = 387–391 | date = March 2001 | pmid = 11268218 | doi = 10.1038/35066610 | s2cid = 2129847 | bibcode = 2001Natur.410..387H }}
Establishment of Sister Chromatid Cohesion 2{{cite journal | vauthors = Bender D, De Silva E, Chen J, Poss A, Gawey L, Rulon Z, Rankin, S | title = Multivalent interaction of ESCO2 with replication machinery is required for sister chromatid cohesion in vertebrates | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 2 | pages = 1081–1089 | date = December 2019 | pmid = 31879348 | pmc = 6969535 | doi = 10.1073/pnas.1911936117 | doi-access = free }}
Flap structure-specific endonuclease 1{{cite journal | vauthors = Henneke G, Koundrioukoff S, Hübscher U | title = Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation | journal = Oncogene | volume = 22 | issue = 28 | pages = 4301–4313 | date = July 2003 | pmid = 12853968 | doi = 10.1038/sj.onc.1206606 | doi-access = free }}{{cite journal | vauthors = Hasan S, Stucki M, Hassa PO, Imhof R, Gehrig P, Hunziker P, Hübscher U, Hottiger MO | title = Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300 | journal = Molecular Cell | volume = 7 | issue = 6 | pages = 1221–1231 | date = June 2001 | pmid = 11430825 | doi = 10.1016/s1097-2765(01)00272-6 | doi-access = free }}{{cite journal | vauthors = Jónsson ZO, Hindges R, Hübscher U | title = Regulation of DNA replication and repair proteins through interaction with the front side of proliferating cell nuclear antigen | journal = The EMBO Journal | volume = 17 | issue = 8 | pages = 2412–2425 | date = April 1998 | pmid = 9545252 | pmc = 1170584 | doi = 10.1093/emboj/17.8.2412 }}{{cite journal | vauthors = Gary R, Ludwig DL, Cornelius HL, MacInnes MA, Park MS | title = The DNA repair endonuclease XPG binds to proliferating cell nuclear antigen (PCNA) and shares sequence elements with the PCNA-binding regions of FEN-1 and cyclin-dependent kinase inhibitor p21 | journal = Journal of Biological Chemistry | volume = 272 | issue = 39 | pages = 24522–24529 | date = September 1997 | pmid = 9305916 | doi = 10.1074/jbc.272.39.24522 | doi-access = free }}{{cite journal | vauthors = Chen U, Chen S, Saha P, Dutta A | title = p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 21 | pages = 11597–11602 | date = October 1996 | pmid = 8876181 | pmc = 38103 | doi = 10.1073/pnas.93.21.11597 | doi-access = free | bibcode = 1996PNAS...9311597C }}{{cite journal | vauthors = Dianova II, Bohr VA, Dianov GL | title = Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair | journal = Biochemistry | volume = 40 | issue = 42 | pages = 12639–12644 | date = October 2001 | pmid = 11601988 | doi = 10.1021/bi011117i }}{{cite journal | vauthors = Yu P, Huang B, Shen M, Lau C, Chan E, Michel J, Xiong Y, Payan DG, Luo Y | title = p15(PAF), a novel PCNA associated factor with increased expression in tumor tissues | journal = Oncogene | volume = 20 | issue = 4 | pages = 484–489 | date = January 2001 | pmid = 11313979 | doi = 10.1038/sj.onc.1204113 | doi-access = free }}
GADD45A{{cite journal | vauthors = Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ | title = Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen | journal = Science | location = New York, N.Y. | volume = 266 | issue = 5189 | pages = 1376–1380 | date = November 1994 | pmid = 7973727 | doi = 10.1126/science.7973727 | bibcode = 1994Sci...266.1376S | url = https://zenodo.org/record/1231241 | type = Submitted manuscript }}{{cite journal | vauthors = Chen IT, Smith ML, O'Connor PM, Fornace AJ | title = Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA | journal = Oncogene | volume = 11 | issue = 10 | pages = 1931–1937 | date = November 1995 | pmid = 7478510 }}{{cite journal | vauthors = Vairapandi M, Azam N, Balliet AG, Hoffman B, Liebermann DA | title = Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 AND Gadd45-mediated negative growth control | journal = Journal of Biological Chemistry | volume = 275 | issue = 22 | pages = 16810–16819 | date = June 2000 | pmid = 10828065 | doi = 10.1074/jbc.275.22.16810 | doi-access = free }}{{cite journal | vauthors = Hall PA, Kearsey JM, Coates PJ, Norman DG, Warbrick E, Cox LS | title = Characterisation of the interaction between PCNA and Gadd45 | journal = Oncogene | volume = 10 | issue = 12 | pages = 2427–2433 | date = June 1995 | pmid = 7784094 }}{{cite journal | vauthors = Yang Q, Manicone A, Coursen JD, Linke SP, Nagashima M, Forgues M, Wang XW | title = Identification of a functional domain in a GADD45-mediated G2/M checkpoint | journal = Journal of Biological Chemistry | volume = 275 | issue = 47 | pages = 36892–36898 | date = November 2000 | pmid = 10973963 | doi = 10.1074/jbc.M005319200 | doi-access = free }}
GADD45G{{cite journal | vauthors = Azam N, Vairapandi M, Zhang W, Hoffman B, Liebermann DA | title = Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control | journal = Journal of Biological Chemistry | volume = 276 | issue = 4 | pages = 2766–2774 | date = January 2001 | pmid = 11022036 | doi = 10.1074/jbc.M005626200 | doi-access = free }}{{cite journal | vauthors = Nakayama K, Hara T, Hibi M, Hirano T, Miyajima A | title = A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth | journal = Journal of Biological Chemistry | volume = 274 | issue = 35 | pages = 24766–24772 | date = August 1999 | pmid = 10455148 | doi = 10.1074/jbc.274.35.24766 | doi-access = free }}
HDAC1{{cite journal | vauthors = Milutinovic S, Zhuang Q, Szyf M | title = Proliferating cell nuclear antigen associates with histone deacetylase activity, integrating DNA replication and chromatin modification | journal = Journal of Biological Chemistry | volume = 277 | issue = 23 | pages = 20974–20978 | date = June 2002 | pmid = 11929879 | doi = 10.1074/jbc.M202504200 | doi-access = free }}
HUS1{{cite journal | vauthors = Komatsu K, Wharton W, Hang H, Wu C, Singh S, Lieberman HB, Pledger WJ, Wang HG | title = PCNA interacts with hHus1/hRad9 in response to DNA damage and replication inhibition | journal = Oncogene | volume = 19 | issue = 46 | pages = 5291–5297 | date = November 2000 | pmid = 11077446 | doi = 10.1038/sj.onc.1203901 | doi-access = free }}
ING1{{cite journal | vauthors = Scott M, Bonnefin P, Vieyra D, Boisvert FM, Young D, Bazett-Jones DP, Riabowol K | title = UV-induced binding of ING1 to PCNA regulates the induction of apoptosis | journal = Journal of Cell Science | volume = 114 | issue = Pt 19 | pages = 3455–3462 | date = October 2001 | pmid = 11682605 | doi = 10.1242/jcs.114.19.3455 }}
KCTD13{{cite journal | vauthors = He H, Tan CK, Downey KM, So AG | title = A tumor necrosis factor alpha- and interleukin 6-inducible protein that interacts with the small subunit of DNA polymerase delta and proliferating cell nuclear antigen | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 21 | pages = 11979–11984 | date = October 2001 | pmid = 11593007 | pmc = 59753 | doi = 10.1073/pnas.221452098 | bibcode = 2001PNAS...9811979H | doi-access = free }}
KIAA0101
Ku70{{cite journal | vauthors = Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T | title = A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein | journal = Journal of Biological Chemistry | volume = 277 | issue = 43 | pages = 40362–40367 | date = October 2002 | pmid = 12171929 | doi = 10.1074/jbc.M206194200 | doi-access = free }}{{cite journal | vauthors = Balajee AS, Geard CR | title = Chromatin-bound PCNA complex formation triggered by DNA damage occurs independent of the ATM gene product in human cells | journal = Nucleic Acids Research | volume = 29 | issue = 6 | pages = 1341–1351 | date = March 2001 | pmid = 11239001 | pmc = 29758 | doi = 10.1093/nar/29.6.1341 }}
Ku80{{cite journal | vauthors = Matheos D, Ruiz MT, Price GB, Zannis-Hadjopoulos M | title = Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1578 | issue = 1–3 | pages = 59–72 | date = October 2002 | pmid = 12393188 | doi = 10.1016/s0167-4781(02)00497-9 }}
MCL1{{cite journal | vauthors = Fujise K, Zhang D, Liu J, Yeh ET | title = Regulation of apoptosis and cell cycle progression by MCL1. Differential role of proliferating cell nuclear antigen | journal = Journal of Biological Chemistry | volume = 275 | issue = 50 | pages = 39458–39465 | date = December 2000 | pmid = 10978339 | doi = 10.1074/jbc.M006626200 | doi-access = free }}
MSH3{{cite journal | vauthors = Kleczkowska HE, Marra G, Lettieri T, Jiricny J | title = hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci | journal = Genes & Development | volume = 15 | issue = 6 | pages = 724–736 | date = March 2001 | pmid = 11274057 | pmc = 312660 | doi = 10.1101/gad.191201 }}{{cite journal | vauthors = Clark AB, Valle F, Drotschmann K, Gary RK, Kunkel TA | title = Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes | journal = Journal of Biological Chemistry | volume = 275 | issue = 47 | pages = 36498–36501 | date = November 2000 | pmid = 11005803 | doi = 10.1074/jbc.C000513200 | doi-access = free }}
MSH6
MUTYH{{cite journal | vauthors = Parker A, Gu Y, Mahoney W, Lee SH, Singh KK, Lu AL | title = Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair | journal = Journal of Biological Chemistry | volume = 276 | issue = 8 | pages = 5547–5555 | date = February 2001 | pmid = 11092888 | doi = 10.1074/jbc.M008463200 | doi-access = free }}
P21{{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–1178 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R | s2cid = 4427026 }}{{cite journal | vauthors = Frouin I, Maga G, Denegri M, Riva F, Savio M, Spadari S, Prosperi E, Scovassi AI | title = Human proliferating cell nuclear antigen, poly(ADP-ribose) polymerase-1, and p21waf1/cip1. A dynamic exchange of partners | journal = Journal of Biological Chemistry | volume = 278 | issue = 41 | pages = 39265–39268 | date = October 2003 | pmid = 12930846 | doi = 10.1074/jbc.C300098200 | doi-access = free }}{{cite journal | vauthors = Gulbis JM, Kelman Z, Hurwitz J, O'Donnell M, Kuriyan J | title = Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA | journal = Cell | volume = 87 | issue = 2 | pages = 297–306 | date = October 1996 | pmid = 8861913 | doi = 10.1016/s0092-8674(00)81347-1 | s2cid = 17461501 | doi-access = free }}{{cite journal | vauthors = Touitou R, Richardson J, Bose S, Nakanishi M, Rivett J, Allday MJ | title = A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome | journal = The EMBO Journal | volume = 20 | issue = 10 | pages = 2367–2375 | date = May 2001 | pmid = 11350925 | pmc = 125454 | doi = 10.1093/emboj/20.10.2367 }}
POLD2{{cite journal | vauthors = Lu X, Tan CK, Zhou JQ, You M, Carastro LM, Downey KM, So AG | title = Direct interaction of proliferating cell nuclear antigen with the small subunit of DNA polymerase delta | journal = Journal of Biological Chemistry | volume = 277 | issue = 27 | pages = 24340–24345 | date = July 2002 | pmid = 11986310 | doi = 10.1074/jbc.M200065200 | doi-access = free }}
POLD3{{cite journal | vauthors = Ducoux M, Urbach S, Baldacci G, Hübscher U, Koundrioukoff S, Christensen J, Hughes P | title = Mediation of proliferating cell nuclear antigen (PCNA)-dependent DNA replication through a conserved p21(Cip1)-like PCNA-binding motif present in the third subunit of human DNA polymerase delta | journal = Journal of Biological Chemistry | volume = 276 | issue = 52 | pages = 49258–49266 | date = December 2001 | pmid = 11595739 | doi = 10.1074/jbc.M106990200 | doi-access = free }}
POLDIP2{{cite journal | vauthors = Liu L, Rodriguez-Belmonte EM, Mazloum N, Xie B, Lee MY | title = Identification of a novel protein, PDIP38, that interacts with the p50 subunit of DNA polymerase delta and proliferating cell nuclear antigen | journal = Journal of Biological Chemistry | volume = 278 | issue = 12 | pages = 10041–10047 | date = March 2003 | pmid = 12522211 | doi = 10.1074/jbc.M208694200 | doi-access = free }}
POLH{{cite journal | vauthors = Haracska L, Johnson RE, Unk I, Phillips B, Hurwitz J, Prakash L, Prakash S | title = Physical and functional interactions of human DNA polymerase eta with PCNA | journal = Molecular and Cellular Biology | volume = 21 | issue = 21 | pages = 7199–7206 | date = November 2001 | pmid = 11585903 | pmc = 99895 | doi = 10.1128/MCB.21.21.7199-7206.2001 }}
POLL{{cite journal | vauthors = Haracska L, Unk I, Johnson RE, Phillips BB, Hurwitz J, Prakash L, Prakash S | title = Stimulation of DNA synthesis activity of human DNA polymerase kappa by PCNA | journal = Molecular and Cellular Biology | volume = 22 | issue = 3 | pages = 784–791 | date = February 2002 | pmid = 11784855 | pmc = 133560 | doi = 10.1128/mcb.22.3.784-791.2002 }}{{cite journal | vauthors = Maga G, Villani G, Ramadan K, Shevelev I, Tanguy Le Gac N, Blanco L, Blanca G, Spadari S, Hübscher U | title = Human DNA polymerase lambda functionally and physically interacts with proliferating cell nuclear antigen in normal and translesion DNA synthesis | journal = Journal of Biological Chemistry | volume = 277 | issue = 50 | pages = 48434–48440 | date = December 2002 | pmid = 12368291 | doi = 10.1074/jbc.M206889200 | doi-access = free | hdl = 10261/338844 | hdl-access = free }}{{cite journal | vauthors = Shimazaki N, Yoshida K, Kobayashi T, Toji S, Tamai K, Koiwai O | title = Over-expression of human DNA polymerase lambda in E. coli and characterization of the recombinant enzyme | journal = Genes to Cells | volume = 7 | issue = 7 | pages = 639–651 | date = July 2002 | pmid = 12081642 | doi = 10.1046/j.1365-2443.2002.00547.x | s2cid = 29714829 }}
RFC1{{cite journal | vauthors = Fotedar R, Mossi R, Fitzgerald P, Rousselle T, Maga G, Brickner H, Messier H, Kasibhatla S, Hübscher U, Fotedar A | title = A conserved domain of the large subunit of replication factor C binds PCNA and acts like a dominant negative inhibitor of DNA replication in mammalian cells | journal = The EMBO Journal | volume = 15 | issue = 16 | pages = 4423–4433 | date = August 1996 | pmid = 8861969 | pmc = 452166 | doi = 10.1002/j.1460-2075.1996.tb00815.x }}{{cite journal | vauthors = Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K | title = A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase | journal = Molecular and Cellular Biology | volume = 22 | issue = 18 | pages = 6509–6520 | date = September 2002 | pmid = 12192049 | pmc = 135621 | doi = 10.1128/mcb.22.18.6509-6520.2002 }}{{cite journal | vauthors = Mossi R, Jónsson ZO, Allen BL, Hardin SH, Hübscher U | title = Replication factor C interacts with the C-terminal side of proliferating cell nuclear antigen | journal = Journal of Biological Chemistry | volume = 272 | issue = 3 | pages = 1769–1776 | date = January 1997 | pmid = 8999859 | doi = 10.1074/jbc.272.3.1769 | doi-access = free }}{{cite journal | vauthors = van der Kuip H, Carius B, Haque SJ, Williams BR, Huber C, Fischer T | title = The DNA-binding subunit p140 of replication factor C is upregulated in cycling cells and associates with G1 phase cell cycle regulatory proteins | journal = Journal of Molecular Medicine | location = Berlin, Germany | volume = 77 | issue = 4 | pages = 386–392 | date = April 1999 | pmid = 10353443 | doi = 10.1007/s001090050365 | s2cid = 22183443 }}
RFC2{{cite journal | vauthors = Cai J, Gibbs E, Uhlmann F, Phillips B, Yao N, O'Donnell M, Hurwitz J | title = 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 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 30 | pages = 18974–18981 | date = July 1997 | pmid = 9228079 | doi = 10.1074/jbc.272.30.18974 | doi-access = free }}{{cite journal | vauthors = Pan ZQ, Chen M, Hurwitz J | title = The subunits of activator 1 (replication factor C) carry out multiple functions essential for proliferating-cell nuclear antigen-dependent DNA synthesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 1 | pages = 6–10 | date = January 1993 | pmid = 8093561 | pmc = 45588 | doi = 10.1073/pnas.90.1.6 | doi-access = free | bibcode = 1993PNAS...90....6P }}
RFC3{{cite journal | vauthors = Merkle CJ, Karnitz LM, Henry-Sánchez JT, Chen J | title = Cloning and characterization of hCTF18, hCTF8, and hDCC1. Human homologs of a Saccharomyces cerevisiae complex involved in sister chromatid cohesion establishment | journal = The Journal of Biological Chemistry | volume = 278 | issue = 32 | pages = 30051–30056 | date = August 2003 | pmid = 12766176 | doi = 10.1074/jbc.M211591200 | doi-access = free }}
RFC4
RFC5
Ubiquitin C{{cite journal | vauthors = Motegi A, Liaw HJ, Lee KY, Roest HP, Maas A, Wu X, Moinova H, Markowitz SD, Ding H, Hoeijmakers JH, Myung K | title = Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 34 | pages = 12411–12416 | date = August 2008 | pmid = 18719106 | pmc = 2518831 | doi = 10.1073/pnas.0805685105 | doi-access = free | bibcode = 2008PNAS..10512411M }}{{cite journal | vauthors = Unk I, Hajdú I, Fátyol K, Hurwitz J, Yoon JH, Prakash L, Prakash S, Haracska L | title = Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 10 | pages = 3768–3773 | date = March 2008 | pmid = 18316726 | pmc = 2268824 | doi = 10.1073/pnas.0800563105 | doi-access = free | bibcode = 2008PNAS..105.3768U }}{{cite journal | vauthors = Brun J, Chiu R, Lockhart K, Xiao W, Wouters BG, Gray DA | title = hMMS2 serves a redundant role in human PCNA polyubiquitination | journal = BMC Molecular Biology | volume = 9 | pages = 24 | date = February 2008 | pmid = 18284681 | pmc = 2263069 | doi = 10.1186/1471-2199-9-24 | doi-access = free }}
Werner syndrome ATP-dependent helicase{{cite journal | vauthors = Rodríguez-López AM, Jackson DA, Nehlin JO, Iborra F, Warren AV, Cox LS | title = Characterisation of the interaction between WRN, the helicase/exonuclease defective in progeroid Werner's syndrome, and an essential replication factor, PCNA | journal = Mechanisms of Ageing and Development | volume = 124 | issue = 2 | pages = 167–174 | date = February 2003 | pmid = 12633936 | doi = 10.1016/s0047-6374(02)00131-8 | s2cid = 37287691 }}{{cite journal | vauthors = Huang S, Beresten S, Li B, Oshima J, Ellis NA, Campisi J | title = Characterization of the human and mouse WRN 3'→5' exonuclease | journal = Nucleic Acids Research | volume = 28 | issue = 12 | pages = 2396–2405 | date = June 2000 | pmid = 10871373 | pmc = 102739 | doi = 10.1093/nar/28.12.2396 }}
XRCC1{{cite journal | vauthors = Fan J, Otterlei M, Wong HK, Tomkinson AE, Wilson DM | title = XRCC1 co-localizes and physically interacts with PCNA | journal = Nucleic Acids Research | volume = 32 | issue = 7 | pages = 2193–2201 | year = 2004 | pmid = 15107487 | pmc = 407833 | doi = 10.1093/nar/gkh556 }}
Y box binding protein 1{{cite journal | vauthors = Ise T, Nagatani G, Imamura T, Kato K, Takano H, Nomoto M, Izumi H, Ohmori H, Okamoto T, Ohga T, Uchiumi T, Kuwano M, Kohno K | title = Transcription factor Y-box binding protein 1 binds preferentially to cisplatin-modified DNA and interacts with proliferating cell nuclear antigen | journal = Cancer Research | volume = 59 | issue = 2 | pages = 342–346 | date = January 1999 | pmid = 9927044 }}

Proteins interacting with PCNA via APIM include human AlkB homologue 2, TFIIS-L, TFII-I, Rad51B, XPA,{{cite journal | vauthors = Gilljam KM, Müller R, Liabakk NB, Otterlei M | title = Nucleotide excision repair is associated with the replisome and its efficiency depends on a direct interaction between XPA and PCNA | journal = PLOS ONE | volume = 7 | issue = 11 | pages = e49199 | date = 2012 | pmid = 23152873 | pmc = 3496702 | doi = 10.1371/journal.pone.0049199 | doi-access = free | bibcode = 2012PLoSO...749199G }} ZRANB3,{{cite journal | vauthors = Ciccia A, Nimonkar AV, Hu Y, Hajdu I, Achar YJ, Izhar L, Petit SA, Adamson B, Yoon JC, Kowalczykowski SC, Livingston DM, Haracska L, Elledge SJ | title = Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress | journal = Molecular Cell | volume = 47 | issue = 3 | pages = 396–409 | date = August 2012 | pmid = 22704558 | pmc = 3613862 | doi = 10.1016/j.molcel.2012.05.024 }} and FBH1.{{cite journal | vauthors = Bacquin A, Pouvelle C, Siaud N, Perderiset M, Salomé-Desnoulez S, Tellier-Lebegue C, Lopez B, Charbonnier JB, Kannouche PL | title = The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells | journal = Nucleic Acids Research | volume = 41 | issue = 13 | pages = 6501–6513 | date = July 2013 | pmid = 23677613 | pmc = 3711418 | doi = 10.1093/nar/gkt397 }}

Uses

Antibodies against proliferating cell nuclear antigen (PCNA) or a similar marker of proliferation 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.{{cite journal | vauthors = Schönenberger F, Deutzmann A, Ferrando-May E, Merhof D | title = Discrimination of cell cycle phases in PCNA-immunolabeled cells | journal = BMC Bioinformatics | volume = 16 | issue = 180 | pages = 180 | date = 29 May 2015 | pmid = 26022740 | pmc = 4448323 | doi = 10.1186/s12859-015-0618-9 | doi-access = free }} 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.{{cite journal | vauthors = Herce HD, Rajan M, Lättig-Tünnemann G, Fillies M, Cardoso MC | title = A novel cell permeable DNA replication and repair marker. | journal = Nucleus | location = Austin, Tex. | volume = 5 | issue = 6 | pages = 590–600 | date = 3 September 2014 | pmid = 25484186 | pmc = 4615156 | doi = 10.4161/nucl.36290 }}

caPCNA, a post-translationally modified isoform of PCNA common in cancer cells, is a potential therapeutic target in cancer therapy.{{cite journal | vauthors = Wang SC | title = PCNA: a silent housekeeper or a potential therapeutic target? | journal = Trends in Pharmacological Sciences | volume = 35 | issue = 4 | pages = 178–186 | date = April 2014 | pmid = 24655521 | doi = 10.1016/j.tips.2014.02.004 }}{{cite journal | vauthors = Gu L, Lingeman R, Yakushijin F, Sun E, Cui Q, Chao J, Hu W, Li H, Hickey RJ, Stark JM, Yuan YC, Chen Y, Vonderfecht SL, Synold TW, Shi Y, Reckamp KL, Horne D, Malkas LH | title = The Anticancer Activity of a First-in-class Small-molecule Targeting PCNA | journal = Clinical Cancer Research | volume = 24 | issue = 23 | pages = 6053–6065 | date = December 2018 | pmid = 29967249 | pmc = 6279569 | doi = 10.1158/1078-0432.CCR-18-0592 }} 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.{{cite journal | vauthors = Gu L, Li M, Li CM, Haratipour P, Lingeman R, Jossart J, Gutova M, Flores L, Hyde C, Kenjić N, Li H, Chung V, Li H, Lomenick B, Von Hoff DD, Synold TW, Aboody KS, Liu Y, Horne D, Hickey RJ, Perry JJ, Malkas LH | title = Small molecule targeting of transcription-replication conflict for selective chemotherapy | journal = Cell Chemical Biology | volume = 30 | issue = 10 | pages = 1235–1247.e6 | date = July 2023 | pmid = 37531956 | pmc = 10592352 | doi = 10.1016/j.chembiol.2023.07.001 | doi-access = free }}

References

External links

{{MeshName|PCNA}}
[https://web.archive.org/web/20120210175011/http://www.antibodypatterns.com/mitotic.php ANA: Cell cycle related (Mitotic): PCNA type 1 and type 2 Antibody Patterns]—Antibody Patterns.com
{{PDBe-KB2|P12004|Proliferating cell nuclear antigen}}

Category:Cell cycle regulators

Category:DNA replication

Category:DNA repair

Category:Proteins