Proliferating cell nuclear antigen (PCNA) is found in every eukaryotic organism and archaea. PCNA is a crucial protein responsible for DNA replication and cell cycle control. PCNA is a DNA polymerase d processing factor and it is also involved in essential cellular functions such as chromatin remodeling, DNA repair, sister chromatid adhesion, and cell cycle regulation. Expression of PCNA is related to proliferation or neoplastic transformation. The PCNA/or its products have been mapped on all the major animals, yeasts, and plants higher than our own - from Arabidopsis, beans, carrots, maize, peas, vinca roses, rapeseed, rice, soybean, and tobacco.
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Physiological Activities of Proliferating Cell Nuclear Antigen (PCNA)
The protein coded by proliferating cell nuclear antigen (PCNA) – its own protein – has remained unchanged for millions of years in all eukaryotic and archaean species that have been studied. PCNA belongs to the DNA sliding clamp complex with the Escherichia coli DNA polymerase (pol) III b subunit and the T4 bacteriophage gene45 protein. The asymmetric charge structure on the surface of the DNA pol III b subunit makes it more likely that monomers are bound to each other and is controlled by the asymmetric poles in the head-to-tail direction. The cavity loop in the middle of the DNA double helix is 3.5 nanometres in diameter. This shorter amino acid chain is what makes PCNA and the bacteriophage T4 gp45 protein lighter. PCNA is a DNA sliding clamp for DNA polymerase delta and required for DNA replication. This protein is also involved in coordinating various cellular activities like DNA repair, cell cycle activity and so on.
Fig. 1 Diagram showing the role of PCNA in DNA synthesis (Strzalka, W., et al. 2011).
Proliferating cell nuclear antigen (PCNA) is a nuclear protein whose main function is cell proliferation. It's involved in DNA replication, repair and recombination.
DNA Replication
DNA polymerase cofactor PCNA can wrap a ring around the DNA chain to form a stable attachment site for DNA polymerase and catalyse DNA synthesis.
DNA Repair
When DNA is repaired, PCNA is recruited to the damage area to support the repair process. It can cooperate with a variety of DNA repair proteins to induce repair.
Cell Cycle Regulation
PCNA mostly appears in the S phase of the cell cycle and is involved in modulating the entrance and growth of the cell cycle. Expression of it is significantly increased during active cell-proliferation.
Gene Expression Regulation
Not only does PCNA function to replicate and repair DNA, but it also appears to be responsible for the regulation of certain genes, including cell growth and differentiation.
Apoptosis
Some researchers reported that PCNA expression was linked to apoptosis and could be involved in cell survival by modulating apoptotic signalling pathways.
Tumor Marker
Because PCNA is the most important factor for cell proliferation, it is used extensively as a biomarker for tumor diagnosis and prognosis. Excessive PCNA expression is often linked to tumour cancer and poor outcome.
Determinants of DNA Replication and Cell Cycle Control
For the replication of DNA, proliferating cell nuclear antigen (PCNA) is a synthesis factor responsible for the rapid and precise synthesis of DNA strands. Because PCNA engages with DNA polymerase delta, it allows replication to continue to generate DNA while the genome stays intact. PCNA controls switching between DNA polymerases at different steps of DNA replication. This process makes sure that the synthesis of DNA is accurate and efficient by coordinating the reactions of various polymerases that form leading and lagging strands. In addition to DNA replication, PCNA is necessary for nucleotide excision repair (NER), which repairs the DNA damage from ultraviolet light and chemicals. PCNA thereby recruits repair factors to the injured area to eliminate and replace injured DNA particles.
Damaged DNA, senescence or cell differentiation (p53-dependent or -independently) release the p21 protein that inhibits the G1–S cell cycle. p21 is attached to CDK via the N-terminal segment and to PCNA via the C-terminal segment. PCNA is a measure as well as an effector of good and bad signals. This is because PCNA cleavage to cyclin-CDK complexes can also transport these regulators to their targets, while knocking them off track by competitive p21 binding indicates the cessation of DNA replication.
Proliferating Cell Nuclear Antigen (PCNA) in DNA Replication
Proliferating cell nuclear antigen (PCNA) was identified as a synthetic factor for the replicative DNA polymerase, which places it at the heart of the replisome. However, other studies have revealed additional roles for this protein in coordinating a complex network of interactions at the replication fork. Pol-α/primase synthesizes the first RNA/DNA primer on the leading strand. Pol δ, together with its synthetic factor PCNA, performs continuous leading strand synthesis; Pol-α/primase participates in RNA priming and discontinuous DNA synthesis of the lagging strand. Completion of Okazaki fragment synthesis requires the synthetic Pol δ (or Pol ϵ) holoenzyme (Pol δ/ϵ, RF-C, and PCNA). Thus, both initiation of leading strand DNA replication and discontinuous lagging strand synthesis require a switch from Pol α to Pol δ (or Pol ϵ). PCNA has been shown to play a central role in coordinating this process. The presence of 3′-OH-terminally bound PCNA prevents reassociation of pol α, and PCNA serves as a specific recruitment signal for the more processive pol δ and pol ϵ.
Proliferating Cell Nuclear Antigen (PCNA) and Chromatin Metabolism
The proliferation cell nuclear antigen (PCNA) is not much flipped over at these replication locations, so it might still be attached to the replication machinery for a couple of Okazaki fragment processes. PCNA binding to CAF-1 has also been genetically investigated in yeast, whose S phase cell cycle displays epigenetic inheritance of DNA and chromatin structure. PCNA gets enticed to the damaged DNA by binding to the p150 subunit of CAF-1.
Proliferating Cell Nuclear Antigen (PCNA) and Gene Expression
Methylated CpG sequences in mammalian genomes are heritable and have gene expression consequences. The gene for inheritance of methylation status is MeCTr. PCNA can attach to MeCTr, so methylation stability within the genome must also be maintained by PCNA.
Proliferating Cell Nuclear Antigen (PCNA) and Apoptosis
The Gadd45 or MyD188 PCNA interaction domain mutants do more apoptotic work if ectopically expressed. Which tells us that when Gadd45 and MyD188 interact with PCNA negative growth control kicks in. Having a ING1 mutant that can't associate with PCNA spares cells from UV-induced cell death.
Proliferating Cell Nuclear Antigen (PCNA) Participates in and Regulates DNA Synthesis
Proliferating cell nuclear antigen (PCNA) - also called cell cycle protein or DNA polymerase delta cofactor — is abundant in non-growing cells, but it is most rapidly produced during the S phase of growing cells. PCNA is stimulated by p53, and the PCNA protein binds to the p53-regulated proteins Gadd45, MyD118, CR6, and most crucially, p21 to decide the fate of cells. Since we now know that PCNA plays a role in DNA replication, this expression pattern could also have a role in regulating DNA synthesis. Its amorphous interactions with other cells emphasize how crucial it is to genome stability and homeostasis. PCNA coordinates a bunch of proteins in a lot of DNA reactions. Many enzymes become more catalytic because they interact with PCNA. PCNA and its bound proteins can be modified after-translationally in other ways too, such as acetylated, SUMOylated, or phosphorylated, either positively or negatively altering the interaction.
References
- Strzalka, W., et al. Proliferating cell nuclear antigen (PCNA): a key factor in DNA replication and cell cycle regulation. Annals of botany. 2011, 107(7): 1127-1140.
- Naryzhny, S. ., et al. Proliferating cell nuclear antigen: a proteomics view. Cellular and molecular life sciences. 2008, 65: 3789-3808.
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