Proliferating cell nuclear antigen (PCNA): a key factor in DNA replication and cell cycle regulation

Abstract

Background: PCNA (proliferating cell nuclear antigen) has been found in the nuclei of yeast, plant and animal cells that undergo cell division, suggesting a function in cell cycle regulation and/or DNA replication. It subsequently became clear that PCNA also played a role in other processes involving the cell genome.

Scope: This review discusses eukaryotic PCNA, with an emphasis on plant PCNA, in terms of the protein structure and its biochemical properties as well as gene structure, organization, expression and function. PCNA exerts a tripartite function by operating as (1) a sliding clamp during DNA synthesis, (2) a polymerase switch factor and (3) a recruitment factor. Most of its functions are mediated by its interactions with various proteins involved in DNA synthesis, repair and recombination as well as in regulation of the cell cycle and chromatid cohesion. Moreover, post-translational modifications of PCNA play a key role in regulation of its functions. Finally, a phylogenetic comparison of PCNA genes suggests that the multi-functionality observed in most species is a product of evolution.

Conclusions: Most plant PCNAs exhibit features similar to those found for PCNAs of other eukaryotes. Similarities include: (1) a trimeric ring structure of the PCNA sliding clamp, (2) the involvement of PCNA in DNA replication and repair, (3) the ability to stimulate the activity of DNA polymerase δ and (4) the ability to interact with p21, a regulator of the cell cycle. However, many plant genomes seem to contain the second, probably functional, copy of the PCNA gene, in contrast to PCNA pseudogenes that are found in mammalian genomes.

Fig. 1.

Structure of Arabidopsis thaliana PCNA1. The three-dimensional model of AtPCNA1 was adapted from the Protein Data Bank (pdb number: 2ZVV). Different colours were used for each subunit: green, yellow and olive. The inter-domain connecting loop and C terminus were coloured in blue and red, respectively. (A) and (B) present the side and front views of the PCNA ring, respectively. The model was generated using PyMol software.

Fig. 2.

Model of eukaryotic DNA replication. PCNA function in DNA synthesis (a cofactor of DNA pol δ/ɛ) and in maturation of the Okazaki fragments is shown (modified from Burges, 2009).

Fig. 3.

Translesion DNA synthesis (TLS). Switch of DNA polymerases is mediated by PCNA (modified from Lehmann, 2003).

Fig. 4.

Model of base excision repair in eukaryotic cells (modified from Kimura and Sakaguchi, 2006).

Fig. 5.

Model of nucleotide excision repair in eukaryotic cells (modified from Kimura and Sakaguchi, 2006). Asterisks mark proteins for which homologues have not yet been found in plants. GGR, global genome repair; TCR, transcription coupled repair.

Fig. 6.

Model of mismatch repair in plant cells (modified from Stojic et al., 2004).

Fig. 7.

Model for interactions of PCNA with proteins regulating the cell cycle, based on studies of mammalian PCNA (adapted from Maga and Hubscher, 2003).

Fig. 8.

PCNA modifications during S phase and their effects on the genome (adapted from Bergink and Jentsch, 2009).