PCNA (proliferating cell nuclear antigen)

2011-10-01   Ivaylo Stoimenov , Thomas Helleday 

Department of Genetics Microbiology, Toxicology, Stockholm University, S-106 91 Stockholm, Sweden (IS, TH); Gray Institute for Radiation Oncology & Biology, University of Oxford, Oxford, OX3 7DQ, UK (TH)




Atlas Image
The localisation of the PCNA gene (in red) at the interface between 20p12.3 and 20p13 histological bands on chromosome 20.


The PCNA gene is situated on human chromosome 20 and it spans about 12 kb. It is a single-copy gene, however, several pseudogenes have been noted. The precise localization of the PCNA gene is at the border of two histological G-bands (p12.3 and p13) (Webb et al., 1990), thus it is reported in both locations depending on the probe used. The human PCNA gene was first cloned and characterized in 1989 by Travali and co-workers (Travali et al., 1989).


There are two reported gene transcripts, which encode the same protein.

 NCBI Reference SequenceLength (unspliced)Length (spliced)ExonsProteinAA
PCNA transcript variant 1NM_002592.211670 bp1355 bp7NP_002583.1261
PCNA transcript variant 2NM_182649.15049 bp1319 bp6NP_872590.1261

PCNA transcript variant 1 is 1355 bp long after the completion of mRNA splicing. It has NCBI Reference Sequence code NM_002592.2 (NCBI). The PCNA transcript variant 1 has seven exons, six of which are contributing to the protein sequence. The first intron is relatively large in comparison with the other PCNA transcript variant. Following the splicing the length of the transcript is shortened to about 12% of that of the initial transcript. The translation starts from the middle of the 2nd exon and ends in the beginning of 7th exon. The product is a full length protein, designated as NP_002583.1 (NCBI), with 261 amino acids.
PCNA transcript variant 2 is 1319 bp long after the completion of mRNA splicing. It has NCBI Reference Sequence code NM_182649.1 (NCBI). The PCNA transcript variant 2 has six exons, which are contributing to the protein sequence. After the splicing the length of the transcript is shortened to about 26% of that of the initial transcript. Translation starts from the end of the 1st exon and ends in the beginning of 7th exon. The product is a full length protein, designated as NP_872590.1 (NCBI), with 261 amino acids.


PCNAP - one pseudogene on human chromosome X - p11 (Ku et al., 1989; Webb et al., 1990).
PCNAP1 and PCNAP2 - two pseudogenes in tandem on human chromosome 4 - q24 (Taniguchi et al., 1996).
There are several other possible pseudogenes:
LOC390102 on chromosome 11 - p15.1 (Webb et al., 1990),
LOC392454 on chromosome X - p11.3 (Ku et al., 1989; Webb et al., 1990).


Atlas Image
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).


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).


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.


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.


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.

Implicated in

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 name
Primary breast cancer
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 name
Chronic lymphoid leukemia (CLL)
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 name
Non-Hodgkins lymphoma
In studies conducting immunohistochemical staining of materials from patients with non-Hodgkins 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 name
Malignant and nonmalignant skin diseases
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 name
Systemic lupus erythematosus (SLE)
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).


Pubmed IDLast YearTitleAuthors
98512461998Proliferating cell nuclear antigen (PCNA) immunolabeling as a prognostic factor in invasive ductal carcinoma of the breast in Taiwan.Chu JS et al
120404362002Expression profile of 11 proteins and their prognostic significance in patients with chronic lymphocytic leukemia (CLL).Faderl S et al
66006141983Clinical features of patients with antibodies directed against proliferating cell nuclear antigen.Fritzler MJ et al
95381671998Long-term prognostic value of PCNA labeling index in primary operable breast cancer.Horiguchi J et al
104820111999Immunohistochemical staining of proliferating cell nuclear antigen (PCNA) in malignant and nonmalignant skin diseases.Kawahira K et al
97119251998Prognostic implications of proliferating cell nuclear antigen (PCNA), AgNORs and P53 in non-Hodgkin's lymphomas.Korkolopoulou P et al
25697651989Human gene for proliferating cell nuclear antigen has pseudogenes and localizes to chromosome 20.Ku DH et al
110938182000Single nucleotide polymorphism analyses of the human proliferating cell nuclear antigen (pCNA) and flap endonuclease (FEN1) genes.Ma X et al
1026921978Autoantibody to a nuclear antigen in proliferating cells.Miyachi K et al
175124022007PCNA, the maestro of the replication fork.Moldovan GL et al
158051172005Proliferating cell nuclear antigen (PCNA) may function as a double homotrimer complex in the mammalian cell.Naryzhny SN et al
187261832008Proliferating cell nuclear antigen: a proteomics view.Naryzhny SN et al
183040012008The biochemistry of somatic hypermutation.Peled JU et al
28824241987Functional identity of proliferating cell nuclear antigen and a DNA polymerase-delta auxiliary protein.Prelich G et al
188544112008Ubiquitylated PCNA plays a role in somatic hypermutation and class-switch recombination and is required for meiotic progression.Roa S et al
194422572009PCNA on the crossroad of cancer.Stoimenov I et al
37451891986An auxiliary protein for DNA polymerase-delta from fetal calf thymus.Tan CK et al
89957621996Cloning, sequencing, and chromosomal localization of two tandemly arranged human pseudogenes for the proliferating cell nuclear antigen (PCNA).Taniguchi Y et al
25653391989Structure of the human gene for the proliferating cell nuclear antigen.Travali S et al
19793111990Localization of the gene for human proliferating nuclear antigen/cyclin by in situ hybridization.Webb G et al
13502261992Prognostic value of proliferating cell nuclear antigen expression in chronic lymphoid leukemia.del Giglio A et al

Other Information

Locus ID:

NCBI: 5111
MIM: 176740
HGNC: 8729
Ensembl: ENSG00000132646


dbSNP: 5111
ClinVar: 5111
TCGA: ENSG00000132646


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
DNA replicationKEGGko03030
Base excision repairKEGGko03410
Nucleotide excision repairKEGGko03420
Mismatch repairKEGGko03430
Cell cycleKEGGko04110
Tight junctionKEGGko04530
DNA replicationKEGGhsa03030
Base excision repairKEGGhsa03410
Nucleotide excision repairKEGGhsa03420
Mismatch repairKEGGhsa03430
Cell cycleKEGGhsa04110
Tight junctionKEGGhsa04530
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
BRCA1-associated genome surveillance complex (BASC)KEGGhsa_M00295
Hepatitis BKEGGhsa05161
BRCA1-associated genome surveillance complex (BASC)KEGGM00295
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G0 and Early G1REACTOMER-HSA-1538133
G1/S TransitionREACTOMER-HSA-69206
G1/S-Specific TranscriptionREACTOMER-HSA-69205
E2F mediated regulation of DNA replicationREACTOMER-HSA-113510
Synthesis of DNAREACTOMER-HSA-69239
DNA strand elongationREACTOMER-HSA-69190
Leading Strand SynthesisREACTOMER-HSA-69109
Polymerase switchingREACTOMER-HSA-69091
Lagging Strand SynthesisREACTOMER-HSA-69186
Processive synthesis on the lagging strandREACTOMER-HSA-69183
Removal of the Flap IntermediateREACTOMER-HSA-69166
Chromosome MaintenanceREACTOMER-HSA-73886
Telomere MaintenanceREACTOMER-HSA-157579
Extension of TelomeresREACTOMER-HSA-180786
Telomere C-strand (Lagging Strand) SynthesisREACTOMER-HSA-174417
Polymerase switching on the C-strand of the telomereREACTOMER-HSA-174411
Processive synthesis on the C-strand of the telomereREACTOMER-HSA-174414
Removal of the Flap Intermediate from the C-strandREACTOMER-HSA-174437
DNA ReplicationREACTOMER-HSA-69306
Base Excision RepairREACTOMER-HSA-73884
Resolution of Abasic Sites (AP sites)REACTOMER-HSA-73933
Resolution of AP sites via the multiple-nucleotide patch replacement pathwayREACTOMER-HSA-110373
PCNA-Dependent Long Patch Base Excision RepairREACTOMER-HSA-5651801
DNA Damage BypassREACTOMER-HSA-73893
Recognition of DNA damage by PCNA-containing replication complexREACTOMER-HSA-110314
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA templateREACTOMER-HSA-110313
Translesion synthesis by REV1REACTOMER-HSA-110312
Translesion Synthesis by POLHREACTOMER-HSA-110320
Translesion synthesis by POLKREACTOMER-HSA-5655862
Translesion synthesis by POLIREACTOMER-HSA-5656121
Termination of translesion DNA synthesisREACTOMER-HSA-5656169
Mismatch RepairREACTOMER-HSA-5358508
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)REACTOMER-HSA-5358565
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)REACTOMER-HSA-5358606
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
Homology Directed RepairREACTOMER-HSA-5693538
HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA)REACTOMER-HSA-5693567
HDR through Homologous Recombination (HRR)REACTOMER-HSA-5685942
Nucleotide Excision RepairREACTOMER-HSA-5696398
Global Genome Nucleotide Excision Repair (GG-NER)REACTOMER-HSA-5696399
Dual Incision in GG-NERREACTOMER-HSA-5696400
Gap-filling DNA repair synthesis and ligation in GG-NERREACTOMER-HSA-5696397
Transcription-Coupled Nucleotide Excision Repair (TC-NER)REACTOMER-HSA-6781827
Dual incision in TC-NERREACTOMER-HSA-6782135
Gap-filling DNA repair synthesis and ligation in TC-NERREACTOMER-HSA-6782210
SUMOylation of DNA replication proteinsREACTOMER-HSA-4615885
TP53 Regulates Transcription of Cell Cycle GenesREACTOMER-HSA-6791312
TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle ArrestREACTOMER-HSA-6804114

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
122266572002RAD6-dependent DNA repair is linked to modification of PCNA by ubiquitin and SUMO.803
151495982004Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage.344
187943472008PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex.199
168882882006Alveolar cell senescence in patients with pulmonary emphysema.137
171150322006Tyrosine phosphorylation controls PCNA function through protein stability.134
209324712010CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation.127
164072522006PCNA is a cofactor for Cdt1 degradation by CUL4/DDB1-mediated N-terminal ubiquitination.124
156165782005Structural basis for recruitment of human flap endonuclease 1 to PCNA.123
210353702010Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage.122
162275862005Nuclear dynamics of PCNA in DNA replication and repair.121


Ivaylo Stoimenov ; Thomas Helleday

PCNA (proliferating cell nuclear antigen)

Atlas Genet Cytogenet Oncol Haematol. 2011-10-01

Online version: http://atlasgeneticsoncology.org/gene/41670/pcna-(proliferating-cell-nuclear-antigen)