Proliferating cell nuclear antigen

Proliferating cell nuclear antigen

The assembled human DNA clamp, a trimer of the protein PCNA.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsPCNA ; MGC8367
External IDsOMIM: 176740 MGI: 97503 HomoloGene: 1945 GeneCards: PCNA Gene
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez511118538
EnsemblENSG00000132646ENSMUSG00000027342
UniProtP12004P17918
RefSeq (mRNA)NM_002592NM_011045
RefSeq (protein)NP_002583NP_035175
Location (UCSC)Chr 20:
5.1 – 5.11 Mb		Chr 2:
132.25 – 132.25 Mb
PubMed search

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]

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

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.[11][12]

PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair (PRR).[13] 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.[14] 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[14] 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.[14] This antagonistic effect occurs because sumoylated PCNA recruits a DNA helicase called Srs2,[15] which has a role in disrupting Rad51 nucleoprotein filaments fundamental for initiation of homologous recombination.

PCNA-binding proteins

 • TCP protein domain  • NKp44 Receptor  • procaspases [16]  • DNA polymerases  • Clamp loader  • Flap endonuclease  • DNA ligase  • Topoisomerase  • Replication licensing factor  • E3 ubiquitin ligases  • E2 SUMO-conjugating enzyme  • Helicases, ATPases  • Mismatch repair enzymes  • Base excision repair enzymes  • Nucleotide excision repair enzyme  • Poly ADP ribose polymerase  • Histone chaperone  • Chromatin remodeling factor  • Histone acetyltransferase  • Histone deacetyltransferase  • DNA methyltransferase  • Sister-chromatid cohesion factors  • Protein kinases  • Cell-cycle regulators  • Apoptotic factors

for details see[17]

Interactions

PCNA has been shown to interact with:

Proteins interacting with PCNA via APIM include human AlkB homologue 2, TFIIS-L, TFII-I, Rad51B,[3] XPA,[78] ZRANB3,[79] and FBH1.[80]

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. 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 obviate 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. [81]

PCNA is a potential therapeutic target in cancer therapy.[82]

See also

External links

References

  1. ↑ Moldovan GL, Pfander B, Jentsch S (May 18, 2007). "PCNA, the maestro of the replication fork.". Cell 129 (4): 665–79. doi:10.1016/j.cell.2007.05.003. PMID 17512402.
  2. ↑ Warbrick E (Mar 1998). "PCNA binding through a conserved motif.". BioEssays : news and reviews in molecular, cellular and developmental biology 20 (3): 195–9. doi:10.1002/(sici)1521-1878(199803)20:3<195::aid-bies2>3.0.co;2-r. PMID 9631646.
  3. ↑ 3.0 3.1 Gilljam KM, Feyzi E, Aas PA, Sousa MM, Müller R, Vågbø CB et al. (Sep 7, 2009). "Identification of a novel, widespread, and functionally important PCNA-binding motif.". The Journal of Cell Biology 186 (5): 645–54. doi:10.1083/jcb.200903138. PMC 2742182. PMID 19736315.
  4. ↑ Mailand N, Gibbs-Seymour I, Bekker-Jensen S (May 2013). "Regulation of PCNA-protein interactions for genome stability.". Nature reviews. Molecular cell biology 14 (5): 269–82. doi:10.1038/nrm3562. PMID 23594953.
  5. ↑ "Entrez Gene: PCNA proliferating cell nuclear antigen".
  6. ↑ Leonardi E, Girlando S, Serio G, Mauri FA, Perrone G, Scampini S et al. (1992). "PCNA and Ki67 expression in breast carcinoma: correlations with clinical and biological variables". J. Clin. Pathol. 45 (5): 416–419. doi:10.1136/jcp.45.5.416. PMC 495304. PMID 1350788.
  7. ↑ Matsumoto K, Moriuchi T, Koji T, Nakane PK (1987). "Molecular cloning of cDNA coding for rat proliferating cell nuclear antigen (PCNA)/cyclin". EMBO J. 6 (3): 637–42. PMC 553445. PMID 2884104.
  8. ↑ 8.0 8.1 Bowman GD, O'Donnell M, Kuriyan J (2004). "Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex". Nature 429 (6993): 724–730. doi:10.1038/nature02585. PMID 15201901.
  9. ↑ 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): 1869–1874. doi:10.1073/pnas.96.5.1869. PMC 26703. PMID 10051561.
  10. ↑ 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 Cell 14 (12): 3225–3236. doi:10.1105/tpc.006403. PMC 151214. PMID 12468739.
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  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 18.7 18.8 18.9 18.10 18.11 18.12 Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T (October 2002). "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". J. Biol. Chem. 277 (43): 40362–7. doi:10.1074/jbc.M206194200. PMID 12171929.
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  69. ↑ 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.
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Further reading

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  • 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.
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  • Kato S, Sekine S, Oh SW, Kim NS, Umezawa Y, Abe N et al. (1995). "Construction of a human full-length cDNA bank". Gene 150 (2): 243–50. doi:10.1016/0378-1119(94)90433-2. PMID 7821789.
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  • Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM et al. (1994). "Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen". Science 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.