| |  |
| |
| | PCNA and mapped interactions with several proteins (D-type of cyclins, CDKN1A, FEN1, RFC complex, polymerase epsilon and polymerase delta). Two residues are highlighted, lysine at position 164 (site of ubiquitylation) and tyrosine at position 211 (site of phosphorylation). |
| |
| Description | The human PCNA protein is a polypeptide of 261 amino acids and theoretical molecular weight of about 29 kDa. The functional protein is a homotrimer, build from three identical units interacting head-to-tail and forming a doughnut shaped molecule. There is an evidence for the existence of a double homotrimer in vivo (Naryzhny et al., 2005). |
| Expression | Expressed in nearly all proliferating tissues with high levels detected in thymus, bone marrow, foetal liver and certain cells of the small intestine and colon. |
| Localisation | PCNA is exclusively localized in the nucleus. It can be detected by immunofluorescence in all proliferating nuclei as discrete nuclear foci, representing sites of ongoing DNA replication and/or DNA repair. |
| Function | PCNA was originally discovered as an antigen, reacting with antibodies derived from sera of patients with systemic lupus erythematosus (Miyachi et al., 1978). The first assigned function of the PCNA protein is as an auxiliary factor of polymerase delta (Tan et al., 1986; Prelich et al., 1987). Later it was suggested that PCNA functions as a cofactor to many other eukaryotic polymerases such as polymerase epsilon, polymerase beta and several specialised polymerases known as translesion synthesis polymerases (eta, kappa, lambda, theta, etc.), with which PCNA is known to interact (Naryzhny, 2008). The role of PCNA in DNA replication is thoroughly investigated and PCNA is proposed to serve as a switch between the priming polymerase alpha and replicative polymerases (delta and epsilon) and functioning as a cofator of the latter polymerases. Complementary to enhancing the processivity of DNA replication, PCNA is known to coordinate the maturation of Okazaki fragments through interaction with FEN1 and stimulation of the flap endonuclease activity. PCNA interacts with large number of proteins, suggesting many functions in vivo (Naryzhny, 2008; Stoimenov and Helleday, 2009). There is evidence, derived from experiments in yeast, that PCNA may be involved in the establishment of sister chromatid cohesion in S phase of the cell cycle (Moldovan et al., 2006). PCNA is an indispensable factor for different DNA repair pathways including mismatch repair, nucleotide excision repair and sub-pathways of base excision repair. There is a growing body of evidence for the function of PCNA in the chromatin remodelling and organisation. The interaction of PCNA and CAF1 is in the heart of the nucleosome assembly, while the chromatin modification is also known to be regulated by PCNA through the known interaction with DNMT1 and HDAC1. One of the most stable interactions of PCNA is that with the cyclin-kinase inhibitor CDKN1A, which suggests a role of PCNA in the cell cycle progression. Another evidence for the involvement of PCNA in the cell cylcle control is the interaction with cyclin-D. Several amino-acid residues are post-translationally modified, suggesting even more complex functions (Stoimenov and Helleday, 2009). PCNA could be subjected to post-translational phosphorylation, acetylation, methylation, ubiquitylation and SUMOylation. |
| Note | |
| Note | The absence of the proliferating nuclear cell antigen (PCNA) protein is embryonic lethal in mice (Roa et al., 2008; Peled et al., 2008). The embryonic lethality in mice also suggests a critical importance of the PCNA protein for humans at least in proliferating tissues (Moldovan et al., 2007). The knockout mice for PCNA (Pcna-/-) are dying in embryonic state, consistent with the role of PCNA in orchestrating DNA replication (Moldovan et al., 2007). In addition to this fact, there are no known mutations of the PCNA protein in humans, which therefore leads to a speculation that PCNA is so vital that any alternation of its sequence would have deleterious consequences. One suggestion for such essential function is the fact that both sequences of the PCNA protein and of the respective gene are highly conserved during evolution (Stoimenov and Helleday, 2009). Indeed, a human population study of PCNA polymorphisms shows only 7 intronic single nucleotide polymorphisms (SNP) and 2 synonymous exonic SNPs (Ma et al., 2000).
According to OMIM and Human Locus Specific Mutation Databases there is no known disease, which is caused by mutation or loss of function of the PCNA protein.
The only implication of PCNA in human disease is as a prognostic or diagnostic marker, sometimes used together with other markers. The utilisation of PCNA as a marker is very much restricted to an illustration of proliferation potential and therefore cannot be specific for any disease. However, PCNA is indeed used as a prognostic and diagnostic marker in several human diseases in clinical practice, as shown below. The list is far from complete since any human disease associated with proliferation could utilise PCNA as a marker. |
| | |
| | |
| Entity | Primary breast cancer |
| Note | A group of patients with high PCNA labeling index was associated with poor overall survival compared with the low PCNA labeling index group in several immunohistochemical studies (Horiguchi et al., 1998; Chu et al., 1998). PCNA labeling index is stated to be an independent predictor in primary breast cancer patients (Horiguchi et al., 1998) with a prognostic value (Chu et al., 1998). |
| | |
| | |
| Entity | Chronic lymphoid leukemia (CLL) |
| Note | There are attempts to correlate the levels of the PCNA protein in cells derived from patients with chronic lymphoid leukemia and the prognosis of survival (del Giglio et al., 1992; Faderl et al., 2002). The high level of PCNA in the cells of CLL patients suggests a higher proliferative activity and potentially shorter survival (del Giglio et al., 1992). Intracellular levels of PCNA protein can be used as marker to predict clinical behaviour and overall survival in patients with CLL (Faderl et al., 2002). |
| | |
| | |
| Entity | Non-Hodgkin's lymphoma |
| Note | In studies conducting immunohistochemical staining of materials from patients with non-Hodgkin's lymphoma, PCNA labeling index together with AgNOR score can be used to predict overall survival (Korkolopoulou et al., 1998). PCNA is the only independent predictor of the post-relapse survival and the histologic grade, which is the most important indicator of disease-free survival (Korkolopoulou et al., 1998). |
| | |
| | |
| Entity | Malignant and nonmalignant skin diseases |
| Note | In one study of comparison between malignant skin diseases (squamous cell carcinoma, adult T lymphotrophic leukemia, mycosis fungoides, malignant melanoma and malignant lymphoma) and nonmalignant skin diseases (resistant atopic dermatitis, psoriasis vulgaris, verruca vulgaris) the anti-PCNA staining was used as a prognostic marker (Kawahira, 1999). The percentage of PCNA-positive cells reported in the study was higher for malignant skin diseases in comparison with the non-malignant skin deseases (Kawahira, 1999). The localization of PCNA-positive cells was found to be in the dermis and the basal layer in case of the malignant skin diseases, whereas in the nonmalignant skin diseases PCNA-positive cells were detected only in the basal layer (Kawahira, 1999). The PCNA labeling index and the distribution of PCNA-positive cells in the skin were suggested to be helpful in the early diagnosis of skin malignancies. |
| | |
| | |
| Entity | Systemic lupus erythematosus (SLE) |
| Note | The anti-PCNA antibodies were originally found in patients with systemic lupus erythematosus (Miyachi et al., 1978), most of whom had diffuse proliferative glomerulonephritis in a small clinical study (Fritzler et al., 1983). |
| | |
| Proliferating cell nuclear antigen (PCNA) immunolabeling as a prognostic factor in invasive ductal carcinoma of the breast in Taiwan. |
| Chu JS, Huang CS, Chang KJ. |
| Cancer Lett. 1998 Sep 25;131(2):145-52. |
| PMID 9851246 |
| |
| Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL). |
| Faderl S, Keating MJ, Do KA, Liang SY, Kantarjian HM, O'Brien S, Garcia-Manero G, Manshouri T, Albitar M. |
| Leukemia. 2002 Jun;16(6):1045-52. |
| PMID 12040436 |
| |
| Clinical features of patients with antibodies directed against proliferating cell nuclear antigen. |
| Fritzler MJ, McCarty GA, Ryan JP, Kinsella TD. |
| Arthritis Rheum. 1983 Feb;26(2):140-5. |
| PMID 6600614 |
| |
| Long-term prognostic value of PCNA labeling index in primary operable breast cancer. |
| Horiguchi J, Iino Y, Takei H, Maemura M, Takeyoshi I, Yokoe T, Ohwada S, Oyama T, Nakajima T, Morishita Y. |
| Oncol Rep. 1998 May-Jun;5(3):641-4. |
| PMID 9538167 |
| |
| Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) in malignant and nonmalignant skin diseases. |
| Kawahira K. |
| Arch Dermatol Res. 1999 Jul-Aug;291(7-8):413-8. |
| PMID 10482011 |
| |
| Prognostic implications of proliferating cell nuclear antigen (PCNA), AgNORs and P53 in non-Hodgkin's lymphomas. |
| Korkolopoulou P, Angelopoulou MK, Kontopidou F, Tsengas A, Patsouris E, Kittas C, Pangalis GA. |
| Leuk Lymphoma. 1998 Aug;30(5-6):625-36. |
| PMID 9711925 |
| |
| Human gene for proliferating cell nuclear antigen has pseudogenes and localizes to chromosome 20. |
| Ku DH, Travali S, Calabretta B, Huebner K, Baserga R. |
| Somat Cell Mol Genet. 1989 Jul;15(4):297-307. |
| PMID 2569765 |
| |
| Single nucleotide polymorphism analyses of the human proliferating cell nuclear antigen (pCNA) and flap endonuclease (FEN1) genes. |
| Ma X, Jin Q, Forsti A, Hemminki K, Kumar R. |
| Int J Cancer. 2000 Dec 15;88(6):938-42. |
| PMID 11093818 |
| |
| Autoantibody to a nuclear antigen in proliferating cells. |
| Miyachi K, Fritzler MJ, Tan EM. |
| J Immunol. 1978 Dec;121(6):2228-34. |
| PMID 102692 |
| |
| PCNA, the maestro of the replication fork. |
| Moldovan GL, Pfander B, Jentsch S. |
| Cell. 2007 May 18;129(4):665-79. (REVIEW) |
| PMID 17512402 |
| |
| Proliferating cell nuclear antigen (PCNA) may function as a double homotrimer complex in the mammalian cell. |
| Naryzhny SN, Zhao H, Lee H. |
| J Biol Chem. 2005 Apr 8;280(14):13888-94. Epub 2005 Feb 1. |
| PMID 15805117 |
| |
| Proliferating cell nuclear antigen: a proteomics view. |
| Naryzhny SN. |
| Cell Mol Life Sci. 2008 Nov;65(23):3789-808. (REVIEW) |
| PMID 18726183 |
| |
| The biochemistry of somatic hypermutation. |
| Peled JU, Kuang FL, Iglesias-Ussel MD, Roa S, Kalis SL, Goodman MF, Scharff MD. |
| Annu Rev Immunol. 2008;26:481-511. (REVIEW) |
| PMID 18304001 |
| |
| Functional identity of proliferating cell nuclear antigen and a DNA polymerase-delta auxiliary protein. |
| Prelich G, Tan CK, Kostura M, Mathews MB, So AG, Downey KM, Stillman B. |
| Nature. 1987 Apr 2-8;326(6112):517-20. |
| PMID 2882424 |
| |
| Ubiquitylated PCNA plays a role in somatic hypermutation and class-switch recombination and is required for meiotic progression. |
| Roa S, Avdievich E, Peled JU, Maccarthy T, Werling U, Kuang FL, Kan R, Zhao C, Bergman A, Cohen PE, Edelmann W, Scharff MD. |
| Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16248-53. Epub 2008 Oct 14. |
| PMID 18854411 |
| |
| PCNA on the crossroad of cancer. |
| Stoimenov I, Helleday T. |
| Biochem Soc Trans. 2009 Jun;37(Pt 3):605-13. |
| PMID 19442257 |
| |
| An auxiliary protein for DNA polymerase-delta from fetal calf thymus. |
| Tan CK, Castillo C, So AG, Downey KM. |
| J Biol Chem. 1986 Sep 15;261(26):12310-6. |
| PMID 3745189 |
| |
| Cloning, sequencing, and chromosomal localization of two tandemly arranged human pseudogenes for the proliferating cell nuclear antigen (PCNA). |
| Taniguchi Y, Katsumata Y, Koido S, Suemizu H, Yoshimura S, Moriuchi T, Okumura K, Kagotani K, Taguchi H, Imanishi T, Gojobori T, Inoko H. |
| Mamm Genome. 1996 Dec;7(12):906-8. |
| PMID 8995762 |
| |
| Structure of the human gene for the proliferating cell nuclear antigen. |
| Travali S, Ku DH, Rizzo MG, Ottavio L, Baserga R, Calabretta B. |
| J Biol Chem. 1989 May 5;264(13):7466-72. |
| PMID 2565339 |
| |
| Localization of the gene for human proliferating nuclear antigen/cyclin by in situ hybridization. |
| Webb G, Parsons P, Chenevix-Trench G. |
| Hum Genet. 1990 Nov;86(1):84-6. |
| PMID 1979311 |
| |
| Prognostic value of proliferating cell nuclear antigen expression in chronic lymphoid leukemia. |
| del Giglio A, O'Brien S, Ford R, Saya H, Manning J, Keating M, Johnston D, Khetan R, el-Naggar A, Deisseroth A. |
| Blood. 1992 May 15;79(10):2717-20. |
| PMID 1350226 |
| |
