Proliferating cell nuclear antigen

PCNA
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

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

Proliferating cell nuclear antigen (PCNA) is a

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

[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

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 nucleoprotein filaments fundamental for initiation of homologous recombination.

PCNA-binding proteins

PCNA interacts with many proteins.^[22]

Interactions

PCNA has been shown to

with:

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

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

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.
  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.
  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.
  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.
  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.
  PMID 1477073
  .
• Krotz D (28 July 2004). "Structure of a clamp–loader complex". 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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  S2CID 27107553
  .

External links

• PCNA at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• ANA: Cell cycle related (Mitotic): PCNA type 1 and type 2 Antibody Patterns—Antibody Patterns.com
• Overview of all the structural information available in the PDB for UniProt: P12004 (Proliferating cell nuclear antigen) at the PDBe-KB.