Proliferating cell nuclear antigen (PCNA): a key factor in DNA replication and cell cycle regulation.
TL;DR: A phylogenetic comparison of PCNA genes suggests that the multi-functionality observed in most species is a product of evolution.
About: This article is published in Annals of Botany.The article was published on 2011-05-01 and is currently open access. It has received 530 citations till now. The article focuses on the topics: Eukaryotic DNA replication & Proliferating cell nuclear antigen.
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TL;DR: Inhibition of PARP is shown to accelerate the speed of replication fork elongation, which prevents fork stalling and induces DNA damage, with implications for genomic instability and cancer treatment and a better understanding of the mechanism of fork speed control.
Abstract: Accurate replication of DNA requires stringent regulation to ensure genome integrity. In human cells, thousands of origins of replication are coordinately activated during S phase, and the velocity of replication forks is adjusted to fully replicate DNA in pace with the cell cycle1. Replication stress induces fork stalling and fuels genome instability2. The mechanistic basis of replication stress remains poorly understood despite its emerging role in promoting cancer2. Here we show that inhibition of poly(ADP-ribose) polymerase (PARP) increases the speed of fork elongation and does not cause fork stalling, which is in contrast to the accepted model in which inhibitors of PARP induce fork stalling and collapse3. Aberrant acceleration of fork progression by 40% above the normal velocity leads to DNA damage. Depletion of the treslin or MTBP proteins, which are involved in origin firing, also increases fork speed above the tolerated threshold, and induces the DNA damage response pathway. Mechanistically, we show that poly(ADP-ribosyl)ation (PARylation) and the PCNA interactor p21Cip1 (p21) are crucial modulators of fork progression. PARylation and p21 act as suppressors of fork speed in a coordinated regulatory network that is orchestrated by the PARP1 and p53 proteins. Moreover, at the fork level, PARylation acts as a sensor of replication stress. During PARP inhibition, DNA lesions that induce fork arrest and are normally resolved or repaired remain unrecognized by the replication machinery. Conceptually, our results show that accelerated replication fork progression represents a general mechanism that triggers replication stress and the DNA damage response. Our findings contribute to a better understanding of the mechanism of fork speed control, with implications for genomic (in)stability and rational cancer treatment.
323 citations
TL;DR: Observations allow us to propose that the in vitro toxic effects of AgNPs on A549 cells are mediated via both ROS-dependent (cytotoxicity) and ROS-independent (cell cycle arrest) pathways.
237 citations
Cites background from "Proliferating cell nuclear antigen ..."
...Down-regulation of PCNA may indicate cell cycle arrest (Strzalka and Ziemienowicz, 2010), the levels of this protein correlate well with other cell proliferation detection methods (Hillegass et al., 2010)....
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...Down-regulation of PCNA may indicate cell cycle arrest (Strzalka and Ziemienowicz, 2010), the levels of this protein correlate well with other cell proliferation detection methods (Hillegass et al....
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TL;DR: Enhanced understanding of DNA repair processes in plants will inform and accelerate the engineering of crop genomes via both traditional and targeted approaches.
Abstract: The genomic integrity of every organism is constantly challenged by endogenous and exogenous DNA-damaging factors. Mutagenic agents cause reduced stability of plant genome and have a deleterious effect on development, and in the case of crop species lead to yield reduction. It is crucial for all organisms, including plants, to develop efficient mechanisms for maintenance of the genome integrity. DNA repair processes have been characterized in bacterial, fungal, and mammalian model systems. The description of these processes in plants, in contrast, was initiated relatively recently and has been focused largely on the model plant Arabidopsis thaliana. Consequently, our knowledge about DNA repair in plant genomes - particularly in the genomes of crop plants - is by far more limited. However, the relatively small size of the Arabidopsis genome, its rapid life cycle and availability of various transformation methods make this species an attractive model for the study of eukaryotic DNA repair mechanisms and mutagenesis. Moreover, abnormalities in DNA repair which proved to be lethal for animal models are tolerated in plant genomes, although sensitivity to DNA damaging agents is retained. Due to the high conservation of DNA repair processes and factors mediating them among eukaryotes, genes and proteins that have been identified in model species may serve to identify homologous sequences in other species, including crop plants, in which these mechanisms are poorly understood. Crop breeding programs have provided remarkable advances in food quality and yield over the last century. Although the human population is predicted to "peak" by 2050, further advances in yield will be required to feed this population. Breeding requires genetic diversity. The biological impact of any mutagenic agent used for the creation of genetic diversity depends on the chemical nature of the induced lesions and on the efficiency and accuracy of their repair. More recent targeted mutagenesis procedures also depend on host repair processes, with different pathways yielding different products. Enhanced understanding of DNA repair processes in plants will inform and accelerate the engineering of crop genomes via both traditional and targeted approaches.
218 citations
Cites background from "Proliferating cell nuclear antigen ..."
...The plant PCNA proteins display many structural and functional similarities to those of other organisms supporting their involvement in the excision repair as well as in the replicative DNA synthesis pathways in plants (Strzalka and Ziemienowicz, 2011)....
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TL;DR: It is found that Icariin could promote MC3T3-E1 osteoblastic cell proliferation and reduce cell apoptosis, associated with increased mRNA levels of positive regulators of cell cycle gene Cyclin E and proliferating cell nuclear antigen (PCNA), decreaed mRNA level of negative regulator gene, Cyclin-dependent kinase 4 inhibitor B (Cdkn2B), and reduced caspase-3 activity.
155 citations
Cites background from "Proliferating cell nuclear antigen ..."
...…of Icariin on osteoblast proliferation and survival and the expression of genes (cyclin E, PCNA, and Cdkn2b) involved in cell cycle by real-time PCR. PCNA is synthesized in early G1 and S phase of the cycle, and serves as an excellent marker of proliferating cells (Strzalka and Ziemienowicz, 2011)....
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TL;DR: Overall, this review suggests that each n-3 PUFA has promising anticancer effects and warrants further research.
Abstract: Breast cancer (BC) is the most common cancer among women worldwide. Dietary fatty acids, especially n-3 polyunsaturated fatty acids (PUFA), are believed to play a role in reducing BC risk. Evidence has shown that fish consumption or intake of long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are beneficial for inhibiting mammary carcinogenesis. The evidence regarding α-linolenic acid (ALA), however, remains equivocal. It is essential to clarify the relation between ALA and cancer since ALA is the principal source of n-3 PUFA in the Western diet and the conversion of ALA to EPA and DHA is not efficient in humans. In addition, the specific anticancer roles of individual n-3 PUFA, alone, have not yet been identified. Therefore, the present review evaluates ALA, EPA and DHA consumed individually as well as in n-3 PUFA mixtures. Also, their role in the prevention of BC and potential anticancer mechanisms of action are examined. Overall, this review suggests that each n-3 PUFA has promising anticancer effects and warrants further research.
150 citations
Cites background from "Proliferating cell nuclear antigen ..."
...Thus, it is involved in DNA replication and repair machinery of the cell [109]....
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...Expression of PCNA is a valid cell proliferation marker since the distribution of PCNA was found to occur during G1, S and G2 phase, but reaches low immunohistochemically detectable levels in M-phase of the cell cycle [106,108,109]....
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References
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TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.
8,339 citations
"Proliferating cell nuclear antigen ..." refers background in this paper
...Regulation of p21 expression is modulated by various factors such as p53 (el-Deiry et al., 1993), MyoD (Guo et al., 1995), STAT (Chin et al., 1996) and Mitosis G2 phase PCNA G1 phase p21 S phase arrest S phase execution S phase Cdk2-cyclin A Cdk2-cyclin E Cdk4,6-cyclin D Cdk1-cyclin B Cdk1-cyclin…...
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TL;DR: It is found that over expression of p21 inhibits the activity of each member of the cyclin/CDK family, and this results indicate that p21 may be a universal inhibitor of cyclin kinases.
Abstract: Deregulation of cell proliferation is a hallmark of neoplastic transformation. Alteration in growth control pathways must translate into changes in the cell-cycle regulatory machinery, but the mechanism by which this occurs is largely unknown. Compared with normal human fibroblasts, cells transformed with a variety of viral oncoproteins show striking changes in the subunit composition of the cyclin-dependent kinases (CDKs). In normal cells, CDKs exist predominantly in multiple quaternary complexes, each containing a CDK, cyclin, proliferating cell nuclear antigen and the p21 protein. However, in many transformed cells, proliferating cell nuclear antigen and p21 are lost from these multiprotein enzymes. Here we have investigated the significance of this phenomenon by molecular cloning of p21 and in vitro reconstitution of the quaternary cell-cycle kinase complexes. We find that p21 inhibits the activity of each member of the cyclin/CDK family. Furthermore, overexpression of p21 inhibits the proliferation of mammalian cells. Our results indicate that p21 may be a universal inhibitor of cyclin kinases.
3,442 citations
"Proliferating cell nuclear antigen ..." refers background in this paper
...The p21 protein has been identified in a complex formed by PCNA, cyclins and cyclindependent kinases (Xiong et al., 1992, 1993)....
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3,266 citations
"Proliferating cell nuclear antigen ..." refers background in this paper
...However, DNA damage and cell ageing lead to production of the p21 protein, which blocks transition from G1 to S phase. p21 achieves this cell cycle arrest between G1 and S phase by inhibiting the activity of cyclin-dependent kinases (Sherr and Roberts, 1995)....
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TL;DR: The molecular mechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed and apoptosis, which eliminates heavily damaged or seriously deregulated cells, is analyzed.
Abstract: DNA damage is a relatively common event in the life of a cell and may lead to mutation, cancer, and cellular or organismic death. Damage to DNA induces several cellular responses that enable the cell either to eliminate or cope with the damage or to activate a programmed cell death process, presumably to eliminate cells with potentially catastrophic mutations. These DNA damage response reactions include: (a) removal of DNA damage and restoration of the continuity of the DNA duplex; (b) activation of a DNA damage checkpoint, which arrests cell cycle progression so as to allow for repair and prevention of the transmission of damaged or incompletely replicated chromosomes; (c) transcriptional response, which causes changes in the transcription profile that may be beneficial to the cell; and (d) apoptosis, which eliminates heavily damaged or seriously deregulated cells. DNA repair mechanisms include direct repair, base excision repair, nucleotide excision repair, double-strand break repair, and cross-link repair. The DNA damage checkpoints employ damage sensor proteins, such as ATM, ATR, the Rad17-RFC complex, and the 9-1-1 complex, to detect DNA damage and to initiate signal transduction cascades that employ Chk1 and Chk2 Ser/Thr kinases and Cdc25 phosphatases. The signal transducers activate p53 and inactivate cyclin-dependent kinases to inhibit cell cycle progression from G1 to S (the G1/S checkpoint), DNA replication (the intra-S checkpoint), or G2 to mitosis (the G2/M checkpoint). In this review the molecular mechanisms of DNA repair and the DNA damage checkpoints in mammalian cells are analyzed.
3,171 citations
"Proliferating cell nuclear antigen ..." refers background in this paper
...5; Sancar et al., 2004; Bray and West, 2005; Kimura and Sakaguchi, 2006)....
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...4; Sancar et al., 2004; Bray and West, 2005; Kimura and Sakaguchi, 2006)....
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TL;DR: Cyclin and the auxiliary protein of DNA polymerase-δ are identical, and it is reported here that these two are identical.
Abstract: Identification of the cellular proteins whose expression is regulated during the cell cycle in normal cells is essential for understanding the mechanisms involved in the control of cell proliferation. A nuclear protein called cyclin of relative molecular mass 36,000 (Mr 36K), whose synthesis correlates with the proliferative state of the cell, has been identified in several cell types of human, mouse, hamster and avian origin. The rate of cyclin synthesis is very low in quiescent cells and increases several fold after serum stimulation shortly before DNA synthesis. Immunofluorescence and autoradiography studies have shown that the nuclear staining patterns of cyclin during S phase have a sequential order of appearance and a clear correlation can be found between DNA synthesis and cyclin positive nuclei. The proliferating cell nuclear antigen (PCNA) and cyclin have many common properties and it has been shown that these two are identical. Recently a protein which is required by DNA polymerase-delta for its catalytic activity with templates having low primer/template ratios has been isolated from calf thymus. We report here that cyclin and the auxiliary protein of DNA polymerase-delta are identical.
1,747 citations
"Proliferating cell nuclear antigen ..." refers background in this paper
...PCNA was first shown to act as a processivity factor of DNA polymerase d, which is required for DNA synthesis during replication (Tan et al., 1986; Bravo et al., 1987; Prelich et al., 1987)....
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