Biology:Proliferating cell nuclear antigen

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
Cryo-EM structure of the DNA-bound PolD–PCNA processive complex

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[16] 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.[16] 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]



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,[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

References

  1. ↑ "PCNA, the maestro of the replication fork". Cell 129 (4): 665–679. May 2007. doi:10.1016/j.cell.2007.05.003. PMID 17512402. 
  2. ↑ "PCNA binding through a conserved motif". BioEssays 20 (3): 195–199. March 1998. doi:10.1002/(sici)1521-1878(199803)20:3<195::aid-bies2>3.0.co;2-r. PMID 9631646. 
  3. ↑ 3.0 3.1 "Identification of a novel, widespread, and functionally important PCNA-binding motif". The Journal of Cell Biology 186 (5): 645–654. September 2009. doi:10.1083/jcb.200903138. PMID 19736315. 
  4. ↑ "Regulation of PCNA-protein interactions for genome stability". Nature Reviews. Molecular Cell Biology 14 (5): 269–282. May 2013. doi:10.1038/nrm3562. PMID 23594953. 
  5. ↑ "Entrez Gene: PCNA proliferating cell nuclear antigen". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5111. 
  6. ↑ "Structural basis for the increased processivity of D-family DNA polymerases in complex with PCNA". Nature Communications 11 (1): 1591. March 2020. doi:10.1038/s41467-020-15392-9. PMID 32221299. Bibcode: 2020NatCo..11.1591M. 
  7. ↑ "PCNA and Ki67 expression in breast carcinoma: correlations with clinical and biological variables". Journal of Clinical Pathology 45 (5): 416–419. May 1992. doi:10.1136/jcp.45.5.416. PMID 1350788. 
  8. ↑ "Molecular cloning of cDNA coding for rat proliferating cell nuclear antigen (PCNA)/cyclin". The EMBO Journal 6 (3): 637–642. March 1987. doi:10.1002/j.1460-2075.1987.tb04802.x. PMID 2884104. 
  9. ↑ "Structural analysis of a eukaryotic sliding DNA clamp-clamp loader complex". Nature 429 (6993): 724–730. June 2004. doi:10.1038/nature02585. PMID 15201901. Bibcode: 2004Natur.429..724B. 
  10. ↑ "Studies on the interactions between human replication factor C and human proliferating cell nuclear antigen". Proceedings of the National Academy of Sciences of the United States of America 96 (5): 1869–1874. March 1999. doi:10.1073/pnas.96.5.1869. PMID 10051561. Bibcode: 1999PNAS...96.1869Z. 
  11. ↑ "Two E2F elements regulate the proliferating cell nuclear antigen promoter differently during leaf development". The Plant Cell 14 (12): 3225–3236. December 2002. doi:10.1105/tpc.006403. PMID 12468739. 
  12. ↑ "HER2 Signaling Drives DNA Anabolism and Proliferation through SRC-3 Phosphorylation and E2F1-Regulated Genes". Cancer Research 76 (6): 1463–1475. March 2016. doi:10.1158/0008-5472.CAN-15-2383. PMID 26833126. 
  13. ↑ "Proliferating cell nuclear antigen is required for DNA excision repair". Cell 69 (2): 367–374. April 1992. doi:10.1016/0092-8674(92)90416-A. PMID 1348971. 
  14. ↑ "Nuclear dynamics of PCNA in DNA replication and repair". Molecular and Cellular Biology 25 (21): 9350–9359. November 2005. doi:10.1128/MCB.25.21.9350-9359.2005. PMID 16227586. 
  15. ↑ "Gaps and forks in DNA replication: Rediscovering old models". DNA Repair 5 (12): 1495–1498. December 2006. doi:10.1016/j.dnarep.2006.07.002. PMID 16956796. http://sro.sussex.ac.uk/id/eprint/545/1/Gaps_and_forks3-07.pdf. 
  16. ↑ 16.0 16.1 16.2 "RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO". Nature 419 (6903): 135–141. September 2002. doi:10.1038/nature00991. PMID 12226657. Bibcode: 2002Natur.419..135H. 
  17. ↑ "SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase". Nature 436 (7049): 428–433. July 2005. doi:10.1038/nature03665. PMID 15931174. Bibcode: 2005Natur.436..428P. 
  18. ↑ "PCNA, the maestro of the replication fork". Cell 129 (4): 665–679. May 2007. doi:10.1016/j.cell.2007.05.003. PMID 17512402. 
  19. ↑ "Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival". The Journal of Experimental Medicine 207 (12): 2631–2645. November 2010. doi:10.1084/jem.20092241. PMID 20975039. 
  20. ↑ 20.00 20.01 20.02 20.03 20.04 20.05 20.06 20.07 20.08 20.09 20.10 20.11 20.12 "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. October 2002. doi:10.1074/jbc.M206194200. PMID 12171929. 
  21. ↑ "A DNA binding winged helix domain in CAF-1 functions with PCNA to stabilize CAF-1 at replication forks". Nucleic Acids Research 44 (11): 5083–5094. June 2016. doi:10.1093/nar/gkw106. PMID 26908650. 
  22. ↑ "A CAF-1-PCNA-mediated chromatin assembly pathway triggered by sensing DNA damage". Molecular and Cellular Biology 20 (4): 1206–1218. February 2000. doi:10.1128/mcb.20.4.1206-1218.2000. PMID 10648606. 
  23. ↑ "Two fundamentally distinct PCNA interaction peptides contribute to chromatin assembly factor 1 function". Molecular and Cellular Biology 29 (24): 6353–6365. December 2009. doi:10.1128/MCB.01051-09. PMID 19822659. 
  24. ↑ "Cdc25C interacts with PCNA at G2/M transition". Oncogene 21 (11): 1717–1726. March 2002. doi:10.1038/sj.onc.1205229. PMID 11896603. 
  25. ↑ "D-type cyclin-binding regions of proliferating cell nuclear antigen". The Journal of Biological Chemistry 269 (15): 11030–11036. April 1994. doi:10.1016/S0021-9258(19)78087-9. PMID 7908906. 
  26. ↑ 26.0 26.1 "Subunit rearrangement of the cyclin-dependent kinases is associated with cellular transformation". Genes & Development 7 (8): 1572–1583. August 1993. doi:10.1101/gad.7.8.1572. PMID 8101826. 
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  28. ↑ "A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4". Nature 366 (6456): 704–707. December 1993. doi:10.1038/366704a0. PMID 8259215. Bibcode: 1993Natur.366..704S. 
  29. ↑ 29.0 29.1 "Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen". Proceedings of the National Academy of Sciences of the United States of America 95 (4): 1392–1397. February 1998. doi:10.1073/pnas.95.4.1392. PMID 9465025. Bibcode: 1998PNAS...95.1392W. 
  30. ↑ "DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci". Nature Genetics 25 (3): 269–277. July 2000. doi:10.1038/77023. PMID 10888872. 
  31. ↑ "PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA". Genes to Cells 7 (10): 997–1007. October 2002. doi:10.1046/j.1365-2443.2002.00584.x. PMID 12354094. 
  32. ↑ "Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1". Science 277 (5334): 1996–2000. September 1997. doi:10.1126/science.277.5334.1996. PMID 9302295. 
  33. ↑ "Transcription coactivator p300 binds PCNA and may have a role in DNA repair synthesis". Nature 410 (6826): 387–391. March 2001. doi:10.1038/35066610. PMID 11268218. Bibcode: 2001Natur.410..387H. 
  34. ↑ "Multivalent interaction of ESCO2 with replication machinery is required for sister chromatid cohesion in vertebrates". Proc. Natl. Acad. Sci. U.S.A. 117 (2): 1081–1089. December 2019. doi:10.1073/pnas.1911936117. PMID 31879348. 
  35. ↑ "Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation". Oncogene 22 (28): 4301–13. July 2003. doi:10.1038/sj.onc.1206606. PMID 12853968. 
  36. ↑ "Regulation of human flap endonuclease-1 activity by acetylation through the transcriptional coactivator p300". Mol. Cell 7 (6): 1221–31. June 2001. doi:10.1016/s1097-2765(01)00272-6. PMID 11430825. 
  37. ↑ 37.0 37.1 "Regulation of DNA replication and repair proteins through interaction with the front side of proliferating cell nuclear antigen". EMBO J. 17 (8): 2412–25. April 1998. doi:10.1093/emboj/17.8.2412. PMID 9545252. 
  38. ↑ "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". J. Biol. Chem. 272 (39): 24522–9. September 1997. doi:10.1074/jbc.272.39.24522. PMID 9305916. 
  39. ↑ "p21Cip1/Waf1 disrupts the recruitment of human Fen1 by proliferating-cell nuclear antigen into the DNA replication complex". Proceedings of the National Academy of Sciences of the United States of America 93 (21): 11597–11602. October 1996. doi:10.1073/pnas.93.21.11597. PMID 8876181. Bibcode: 1996PNAS...9311597C. 
  40. ↑ "Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair". Biochemistry 40 (42): 12639–12644. October 2001. doi:10.1021/bi011117i. PMID 11601988. 
  41. ↑ 41.0 41.1 41.2 "p15(PAF), a novel PCNA associated factor with increased expression in tumor tissues". Oncogene 20 (4): 484–489. January 2001. doi:10.1038/sj.onc.1204113. PMID 11313979. 
  42. ↑ "Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen". Science 266 (5189): 1376–80. November 1994. doi:10.1126/science.7973727. PMID 7973727. Bibcode: 1994Sci...266.1376S. https://zenodo.org/record/1231241. 
  43. ↑ "Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA". Oncogene 11 (10): 1931–7. November 1995. PMID 7478510. 
  44. ↑ "Characterization of MyD118, Gadd45, and proliferating cell nuclear antigen (PCNA) interacting domains. PCNA impedes MyD118 AND Gadd45-mediated negative growth control". J. Biol. Chem. 275 (22): 16810–9. June 2000. doi:10.1074/jbc.275.22.16810. PMID 10828065. 
  45. ↑ "Characterisation of the interaction between PCNA and Gadd45". Oncogene 10 (12): 2427–33. June 1995. PMID 7784094. 
  46. ↑ "Identification of a functional domain in a GADD45-mediated G2/M checkpoint". J. Biol. Chem. 275 (47): 36892–8. November 2000. doi:10.1074/jbc.M005319200. PMID 10973963. 
  47. ↑ "Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control". J. Biol. Chem. 276 (4): 2766–74. January 2001. doi:10.1074/jbc.M005626200. PMID 11022036. 
  48. ↑ "A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth". J. Biol. Chem. 274 (35): 24766–72. August 1999. doi:10.1074/jbc.274.35.24766. PMID 10455148. 
  49. ↑ "Proliferating cell nuclear antigen associates with histone deacetylase activity, integrating DNA replication and chromatin modification". J. Biol. Chem. 277 (23): 20974–8. June 2002. doi:10.1074/jbc.M202504200. PMID 11929879. 
  50. ↑ "PCNA interacts with hHus1/hRad9 in response to DNA damage and replication inhibition". Oncogene 19 (46): 5291–7. November 2000. doi:10.1038/sj.onc.1203901. PMID 11077446. 
  51. ↑ "UV-induced binding of ING1 to PCNA regulates the induction of apoptosis". J. Cell Sci. 114 (Pt 19): 3455–62. October 2001. doi:10.1242/jcs.114.19.3455. PMID 11682605. 
  52. ↑ "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". Proc. Natl. Acad. Sci. U.S.A. 98 (21): 11979–84. October 2001. doi:10.1073/pnas.221452098. PMID 11593007. Bibcode: 2001PNAS...9811979H. 
  53. ↑ 53.0 53.1 "Chromatin-bound PCNA complex formation triggered by DNA damage occurs independent of the ATM gene product in human cells". Nucleic Acids Res. 29 (6): 1341–51. March 2001. doi:10.1093/nar/29.6.1341. PMID 11239001. 
  54. ↑ "Ku antigen, an origin-specific binding protein that associates with replication proteins, is required for mammalian DNA replication". Biochim. Biophys. Acta 1578 (1–3): 59–72. October 2002. doi:10.1016/s0167-4781(02)00497-9. PMID 12393188. 
  55. ↑ "Regulation of apoptosis and cell cycle progression by MCL1. Differential role of proliferating cell nuclear antigen". J. Biol. Chem. 275 (50): 39458–65. December 2000. doi:10.1074/jbc.M006626200. PMID 10978339. 
  56. ↑ 56.0 56.1 "hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci". Genes Dev. 15 (6): 724–36. March 2001. doi:10.1101/gad.191201. PMID 11274057. 
  57. ↑ 57.0 57.1 "Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes". J. Biol. Chem. 275 (47): 36498–501. November 2000. doi:10.1074/jbc.C000513200. PMID 11005803. 
  58. ↑ "Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair". J. Biol. Chem. 276 (8): 5547–55. February 2001. doi:10.1074/jbc.M008463200. PMID 11092888. 
  59. ↑ 59.0 59.1 "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". EMBO J. 15 (16): 4423–33. August 1996. doi:10.1002/j.1460-2075.1996.tb00815.x. PMID 8861969. 
  60. ↑ "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. October 2005. doi:10.1038/nature04209. PMID 16189514. Bibcode: 2005Natur.437.1173R. 
  61. ↑ "Human proliferating cell nuclear antigen, poly(ADP-ribose) polymerase-1, and p21waf1/cip1. A dynamic exchange of partners". J. Biol. Chem. 278 (41): 39265–8. October 2003. doi:10.1074/jbc.C300098200. PMID 12930846. 
  62. ↑ "Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA". Cell 87 (2): 297–306. October 1996. doi:10.1016/s0092-8674(00)81347-1. PMID 8861913. 
  63. ↑ "A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome". EMBO J. 20 (10): 2367–75. May 2001. doi:10.1093/emboj/20.10.2367. PMID 11350925. 
  64. ↑ "Direct interaction of proliferating cell nuclear antigen with the small subunit of DNA polymerase delta". J. Biol. Chem. 277 (27): 24340–5. July 2002. doi:10.1074/jbc.M200065200. PMID 11986310. 
  65. ↑ "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". J. Biol. Chem. 276 (52): 49258–66. December 2001. doi:10.1074/jbc.M106990200. PMID 11595739. 
  66. ↑ "Identification of a novel protein, PDIP38, that interacts with the p50 subunit of DNA polymerase delta and proliferating cell nuclear antigen". J. Biol. Chem. 278 (12): 10041–7. March 2003. doi:10.1074/jbc.M208694200. PMID 12522211. 
  67. ↑ "Physical and functional interactions of human DNA polymerase eta with PCNA". Mol. Cell. Biol. 21 (21): 7199–206. November 2001. doi:10.1128/MCB.21.21.7199-7206.2001. PMID 11585903. 
  68. ↑ "Stimulation of DNA synthesis activity of human DNA polymerase kappa by PCNA". Mol. Cell. Biol. 22 (3): 784–91. February 2002. doi:10.1128/mcb.22.3.784-791.2002. PMID 11784855. 
  69. ↑ "Human DNA polymerase lambda functionally and physically interacts with proliferating cell nuclear antigen in normal and translesion DNA synthesis". J. Biol. Chem. 277 (50): 48434–40. December 2002. doi:10.1074/jbc.M206889200. PMID 12368291. 
  70. ↑ "Over-expression of human DNA polymerase lambda in E. coli and characterization of the recombinant enzyme". Genes Cells 7 (7): 639–51. July 2002. doi:10.1046/j.1365-2443.2002.00547.x. PMID 12081642. 
  71. ↑ "A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase". Mol. Cell. Biol. 22 (18): 6509–20. September 2002. doi:10.1128/mcb.22.18.6509-6520.2002. PMID 12192049. 
  72. ↑ 72.0 72.1 "Replication factor C interacts with the C-terminal side of proliferating cell nuclear antigen". J. Biol. Chem. 272 (3): 1769–76. January 1997. doi:10.1074/jbc.272.3.1769. PMID 8999859. 
  73. ↑ "The DNA-binding subunit p140 of replication factor C is upregulated in cycling cells and associates with G1 phase cell cycle regulatory proteins". J. Mol. Med. 77 (4): 386–92. April 1999. doi:10.1007/s001090050365. PMID 10353443. 
  74. ↑ 74.0 74.1 74.2 "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". The Journal of Biological Chemistry 272 (30): 18974–18981. July 1997. doi:10.1074/jbc.272.30.18974. PMID 9228079. 
  75. ↑ "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. doi:10.1073/pnas.90.1.6. PMID 8093561. Bibcode: 1993PNAS...90....6P. 
  76. ↑ "Cloning and characterization of hCTF18, hCTF8, and hDCC1. Human homologs of a Saccharomyces cerevisiae complex involved in sister chromatid cohesion establishment". The Journal of Biological Chemistry 278 (32): 30051–30056. August 2003. doi:10.1074/jbc.M211591200. PMID 12766176. 
  77. ↑ "Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks". Proceedings of the National Academy of Sciences of the United States of America 105 (34): 12411–12416. August 2008. doi:10.1073/pnas.0805685105. PMID 18719106. Bibcode: 2008PNAS..10512411M. 
  78. ↑ "Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination". Proceedings of the National Academy of Sciences of the United States of America 105 (10): 3768–3773. March 2008. doi:10.1073/pnas.0800563105. PMID 18316726. Bibcode: 2008PNAS..105.3768U. 
  79. ↑ "hMMS2 serves a redundant role in human PCNA polyubiquitination". BMC Molecular Biology 9: 24. February 2008. doi:10.1186/1471-2199-9-24. PMID 18284681. 
  80. ↑ "Characterisation of the interaction between WRN, the helicase/exonuclease defective in progeroid Werner's syndrome, and an essential replication factor, PCNA". Mechanisms of Ageing and Development 124 (2): 167–174. February 2003. doi:10.1016/s0047-6374(02)00131-8. PMID 12633936. 
  81. ↑ "Characterization of the human and mouse WRN 3'-->5' exonuclease". Nucleic Acids Research 28 (12): 2396–2405. June 2000. doi:10.1093/nar/28.12.2396. PMID 10871373. 
  82. ↑ "XRCC1 co-localizes and physically interacts with PCNA". Nucleic Acids Res. 32 (7): 2193–201. 2004. doi:10.1093/nar/gkh556. PMID 15107487. 
  83. ↑ "Transcription factor Y-box binding protein 1 binds preferentially to cisplatin-modified DNA and interacts with proliferating cell nuclear antigen". Cancer Research 59 (2): 342–346. January 1999. PMID 9927044. 
  84. ↑ "Nucleotide excision repair is associated with the replisome and its efficiency depends on a direct interaction between XPA and PCNA". PLOS ONE 7 (11): e49199. 2012. doi:10.1371/journal.pone.0049199. PMID 23152873. Bibcode: 2012PLoSO...749199G. 
  85. ↑ "Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress". Molecular Cell 47 (3): 396–409. August 2012. doi:10.1016/j.molcel.2012.05.024. PMID 22704558. 
  86. ↑ "The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells". Nucleic Acids Research 41 (13): 6501–6513. July 2013. doi:10.1093/nar/gkt397. PMID 23677613. 
  87. ↑ "Discrimination of cell cycle phases in PCNA-immunolabeled cells". BMC Bioinform. 16 (180): 180. 29 May 2015. doi:10.1186/s12859-015-0618-9. PMID 26022740. 
  88. ↑ "A novel cell permeable DNA replication and repair marker.". Nucleus (Austin, Tex.) 5 (6): 590–600. 3 September 2014. doi:10.4161/nucl.36290. PMID 25484186. 
  89. ↑ "PCNA: a silent housekeeper or a potential therapeutic target?". Trends in Pharmacological Sciences 35 (4): 178–186. April 2014. doi:10.1016/j.tips.2014.02.004. PMID 24655521. 
  90. ↑ "The Anticancer Activity of a First-in-class Small-molecule Targeting PCNA". Clinical Cancer Research 24 (23): 6053–6065. December 2018. doi:10.1158/1078-0432.CCR-18-0592. PMID 29967249. 
  91. ↑ "Small molecule targeting of transcription-replication conflict for selective chemotherapy". Cell Chemical Biology 30 (10): 1235–1247.e6. July 2023. doi:10.1016/j.chembiol.2023.07.001. PMID 37531956. 

Further reading

External links



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