The PCNA pseudogenes in the human genome
© Stoimenov and Lagerqvist; licensee BioMed Central Ltd. 2012
Received: 11 October 2011
Accepted: 6 February 2012
Published: 6 February 2012
The proliferating cell nuclear antigen (PCNA) is a key protein in the eukaryotic DNA replication and cell proliferation. Following the cloning and characterisation of the human PCNA gene, the question of the existence of pseudogenes in the human genome was raised.
In this short communication we summarise the existing information about the PCNA pseudogenes and critically assess their status.
We propose the existence of at least four valid PCNA pseudogenes, PCNAP1, PCNAP2, LOC392454 and LOC390102. We would like to recommend assignment of a name for LOC392454 as "proliferating cell nuclear antigen pseudogene 3" (alias PCNAP3) and a name for LOC390102 as "proliferating cell nuclear antigen pseudogene 4" (alias PCNAP4). We prompt for more critical evaluation of the existence of a PCNA pseudogene, designated as PCNAP.
The proliferating cell nuclear antigen (PCNA) is a key protein in the eukaryotic DNA replication and cell proliferation. The first observation of PCNA as an antigen in sera, isolated from patients with systemic lupus erythematosus, started a new field of research . Already in this pioneering investigation, the function of PCNA in cellular proliferation was revealed, however the true nature of the antigen was not known. The identification of PCNA as an auxiliary protein to DNA polymerase delta [2, 3], placed PCNA as a protein of a vital importance and prompted the question of gene characterisation. In the same year, the human cDNA encoding the PCNA protein was cloned and characterised . The molecular cloning of the human PCNA gene followed soon, hinting for a possibility for existence of a PCNA pseudogene in the genome . The PCNA gene was mapped to a locus in human chromosome 20 [6, 7]. An interesting serendipity of the gene localisation was the discovery of several related to PCNA loci, which were proposed to contain pseudogenes of PCNA [6, 7]. Since then, several reports of PCNA pseudogenes have been published [5–9]. However, the current state and validity of those pseudogenes is an open question. There is considerable discrepancy between the major human-related databases and the experimental data. In this short communication we summarise the evidence for the PCNA pseudogenes and try to validate their status.
The first paper (Paper I) characterises the PCNA gene, however, it mentions a possible PCNA pseudogene . The follow-up paper from the same group (Paper II) describes this PCNA pseudogene in detail . Paper I reports that in a total genomic EcoRI digest of human DNA, three distinct fragments can be detected by hybridization with a full length cDNA probe, derived from the human PCNA sequence. These fragments are with size 3.7 kb, 2.7 kb and 1.5 kb . The larger fragments (3.7 kb and 2.7 kb) can originate from the PCNA gene, however, the smallest fragment (1.5 kb) was proposed to be a product of a PCNA pseudogene . Indeed, in Paper II the existence of this the pseudogene was confirmed and its sequence was published . The sequence lacks introns and possesses the characteristics of processed pseudogenes or nonviral retrotransposons . This PCNA pseudogene was mapped to the human chromosome X in the region Xpter-Xq13. In Paper II, another possible locus for a PCNA pseudogene was hypothesised to exist, situated on the human chromosome 6. The authors show detection of a PCNA related sequence in one of the mouse-human somatic cell hybrid clones (N9) which retained human chromosomes 6, 7, 21 and partial 17 . The presence of a PCNA related sequence on chromosome 6 was investigated in another of the authors' experiments, however, the vague and non-aligned hybridisation of a full length PCNA probe to chromosome 6, presented in the paper suggests merely an artifact . An interesting conclusion from the results in the Paper II is that if there is a PCNA pseudogene on chromosome 6, it does not contain introns, as is the case with the PCNA pseudogene on chromosome X. The only strong evidence presented in the paper for existence of a PCNA pseudogene on chromosome 6 is the clone N9. However, in our opinion a careful characterization of the N9 clone is needed in order to exclude the presence of fragments of other human chromosomes (11, 20 and X). The argument for such characterization of the N9 clone is the next important paper (Paper III), which maps the chromosomal location of the PCNA gene and two of the PCNA pseudogenes .
Indeed, in Paper III, the presence of a PCNA pseudogene on chromosome 6 was not detected . In Paper III the localisation experiments for the PCNA gene and its pseudogenes are conducted by using a probe, derived from a fragment of the human PCNA cDNA. The results revealed a presence of three loci, hybridising with the probe-the PCNA gene (chromosome 20), and two pseudogenes-on chromosome X and chromosome 11. The PCNA pseudogene on chromosome X is mapped in the region Xp11.3-Xp11.4, which not only confirms the location presented in Paper II, but gives a more precise location of the proposed PCNA pseudogene. The presence of a sequence which anneals with the probe on chromosome 11 in the region 11p15.1, represent another PCNA pseudogene.
The fourth publication (Paper IV) presents new PCNA pseudogenes , which are further characterised in the follow-up study by the same group (Paper V) . Both papers IV and V supply strong evidence for the existence of PCNA pseudogenes on chromosome 4 in the region 4q24. The two sequences described in the paper have already been assigned names by HUGO, "proliferating cell nuclear antigen pseudogene 1" (PCNAP1) and "proliferating cell nuclear antigen pseudogene 2" (PCNAP2). The existence of PCNA pseudogenes on human chromosome 4 was proposed earlier by the same group in Paper IV, but the later paper presents a more detailed study and sequence of the PCNA pseudogenes. Webb et al. failed to detect PCNA pseudogenes on the human chromosome 4, possibly because of the limitation of the probe used . In fact PCNAP2 is a fragment which contains sequences homologous to exon 4 and 5 of the PCNA gene .
In the HUGO database , maintained by HUGO Gene Nomenclature Committee (HGNC), there are currently three active entries for PCNA pseudogenes: PCNAP , PCNAP1  and PCNAP2 . The PCNAP, PCNAP1 and PCNAP2 are present as PCNA pseudogenes in the NCBI GENE database  together with LOC392454 and LOC390102 .
PCNAP1 and PCNAP2 refer to the PCNA pseudogene sequences published in Paper V.
The LOC390102 is in the same locus as the PCNA pseudogene, described in Paper III and mapped on chromosome 11 (region 11p15.1). Webb et al. did not publish a sequence of the PCNA gene located on chromosome 11, however their method of detection proved to be valid for localisation of the PCNA gene and the PCNA pseudogene on chromosome X. Since the localisation of the PCNA pseudogene, described by Webb at al. is in the precise localisation region of LOC390102, and there are no known PCNA pseudogenes in close vicinity, we speculate that LOC390102 is indeed the PCNA pseudogene, detected by Webb et al. in 1990. If LOC390102 indeed represents a valid PCNA pseudogene, we recommend assignment of a name for LOC390102 as "proliferating cell nuclear antigen pseudogene 4" and the alias PCNAP4.
The priority of PCNAP3 to PCNAP4 is given on the basis of the first date of publication of the evidences for existence of the respective PCNA pseudogenes.
The result from a pair-wise alignment between the sequences of PCNA gene and the proposed PCNA pseudogenes
Identities towards PCNA
Gaps towards PCNA
Despite of the possibility of representing valid human PCNA pseudogenes, an interesting question is whether the sequences of PCNAP, PCNAP1, PCNAP2, LOC392454 and LOC390102 are present in the human trascriptome. In order to address this question, we checked for mRNA transcripts and expressed sequence tagged (EST) transcripts, associated with the corresponding sequences of the human PCNA pseudogenes. We were unable to find the sequences of any of the PCNA pseudogenes as stand-alone mRNA transcripts. However, when we checked the transcription profile of a respective genomic stretch in the UCSC genome browser , we found that a partial sequence of PCNAP1 is present in the A1223432, DA828011, FN062437 and CR743211 human EST transcripts. The sequence of LOC392454 was partially present in the human H79841 EST transcript. There are no ESTs matches with the sequences of PCNAP, PCNAP2 or LOC390102. Despite of the existence of EST transcripts which matched the sequence of the PCNA pseudogenes, we would like to express caution in the interpretation of such results. ESTs libraries are prone to non-mRNA contamination including genomic DNA, and it is possible that the regions of interest are not transcribed at all . We also performed a BLAST search in the human ESTs database targeting the sequences of the proposed PCNA pseudogenes, and although we detected matches we could not conclude with certainty if the sequences of the PCNA pseudogenes are transcribed or not.
In summary we propose the existence of at least four valid PCNA pseudogenes, PCNAP1, PCNAP2, LOC392454 and LOC390102. We would like to recommend assignment of a name for LOC392454 as "proliferating cell nuclear antigen pseudogene 3" (alias PCNAP3) and a name for LOC390102 as "proliferating cell nuclear antigen pseudogene 4" (alias PCNAP4). We prompt for more critical evaluation of the existence of a PCNA pseudogene, designated as PCNAP.
restriction endonuclease I from Escherichia coli
Human Genome Organisation
National Center for Biotechnology Information
Proliferating Cell Nuclear Antigen
Proliferating Cell Nuclear Antigen Pseudogene
Proliferating Cell Nuclear Antigen Pseudogene 1
Proliferating Cell Nuclear Antigen Pseudogene 2.
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