Proliferating cell nuclear antigen

Proliferating Cell Nuclear Antigen, commonly known as PCNA, is a protein that acts as a processivity factor for DNA polymerase δ in eukaryotic cells. It achieves this processivity by encircling the DNA, thus creating a topological link to the genome. It is an example of a DNA clamp.

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]

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.^[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 E2F transcription 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][8]

PCNA is also involved in the DNA damage tolerance pathway known as post-replication repair (PRR).^[9] 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.^[10] 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^[10] 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.^[10] This antagonistic effect occurs because sumoylated PCNA recruits a DNA helicase called Srs2,^[11] which has a role in disrupting Rad51 nucleoprotein filaments fundamental for initiation of homologous recombination.

PCNA-binding proteins

NKp44 Receptor, 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 ^[12]

Interactions

PCNA has been shown to interact with Ku70,^[13][14] MSH3,^[13][15][16] Werner syndrome ATP-dependent helicase,^[17][18] RFC2,^[13][19][20] RFC3,^[13][21] RFC1,^{[13][22][23][24][25]} RFC4,^[13][19] RFC5,^[13][19][24] GADD45G,^[26][27] CDC25C,^[28] MUTYH,^[29] Flap structure-specific endonuclease 1,^{[30][31][32][33][34][35][36]} Cyclin O,^[13][37] CHTF18,^[13] Y box binding protein 1,^[38] Cyclin D1,^[39][40] Annexin A2,^[13] MSH6,^[13][15][16] DNMT1,^[41][42][43] HDAC1,^[44] KCTD13,^[45] XRCC1,^[46] Cyclin-dependent kinase 4,^[40][47] Ku80,^[13][14][48] HUS1,^[49] GADD45A,^{[50][51][52][53][54]} POLD2,^[55] ING1,^[56] POLH,^[57] KIAA0101,^[36] POLDIP2,^[58] EP300,^[59] MCL1,^[60] POLD3,^[13][61] Cyclin-dependent kinase inhibitor 1C,^[62] POLL,^[63][64][65] Ubiquitin C^[66][67][68] and P21.^{[23][32][36][62][69][70][71][72]}

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.

See also

• Transcription
• Ki-67 - cellular marker for proliferation

External links

• MeSH PCNA
• "ANA: Cell cycle related (Mitotic): PCNA type 1 and type 2 Antibody Patterns". Antibody Patterns.com. http://www.antibodypatterns.com/mitotic.php. Retrieved 2008-04-15. 
• Dan Krotz. "Structure of a clamp–loader complex". Advanced Light Source News. Lawrence Berkeley National Laboratory. http://www-als.lbl.gov/als/science/sci_archive/80slidingclamp.html. Retrieved 2008-04-15. ^[4]
• "Movie showing a model of clamp loading of PCNA onto DNA". Pubmed Central. http://www.pubmedcentral.gov/picrender.fcgi?artid=1236569&blobname=pnas_0506447102_06447Movie2.mov. ^[73]

References

Further reading