The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro

Prelich, Gregory; Kostura, Matthew; Marshak, Daniel R.; Mathews, Michael B.; Stillman, Bruce

doi:10.1038/326471a0

Cited by 473 publications

(269 citation statements)

References 38 publications

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“…Recent studies have shown PCNA to be involved in numerous cellular functions associated with cell proliferation and to directly bind to or interact with various proteins, as listed in Table 1 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)24). Our previous study (24) revealed that the PCNA multiprotein complexes purified by mAb to PCNA contained components of multiprotein machinery such as the DNA replication fork (Figure 1) (12,13,21,22) and a quaternary PCNA/ p21/CDK/cyclin complex reported to play a key role in the regulation of the cell cycle (14,17).…”

Section: Discussionmentioning

confidence: 99%

Autoimmune responses to proliferating cell nuclear antigen multiprotein complexes involved in cell proliferation are strongly associated with their structure and biologic function in patients with systemic lupus erythematosus

Kogure

Takasaki

Takeuchi

et al. 2002

Arthritis & Rheumatism

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Objective. To analyze the reaction of lupus sera with proliferating cell nuclear antigen (PCNA) multiprotein complexes (PCNA complexes), which are part of the protein machinery involved in cell proliferation.Methods. PCNA complexes were purified from rabbit thymus extract by affinity chromatography using anti-PCNA monoclonal antibodies (TOB7, TO17, and TO30); monomeric and trimeric PCNA forms (AK-PCNA) were purified using anti-PCNA serum AK. The reactions to these antigens of 10 anti-PCNA-positive and 40 anti-PCNA-negative sera selected from 560 lupus patients were tested by immunoblotting, immunoprecipitation, and enzyme-linked immunosorbent assays (ELISAs).Results. With one exception (serum OK), anti-PCNA-positive sera reacted exclusively with only the 34-kd polypeptide. In contrast, 14 of 40 anti-PCNAnegative sera reacted with multiple proteins within PCNA complexes. Most anti-PCNA-positive sera probably recognize as epitopes the binding sites for other proteins on PCNA, which are likely hidden when PCNA is complexed with other proteins. As a consequence, only serum OK reacted with the PCNA complex in a series of ELISAs. Using AK-PCNA as a competitive inhibitor, it was determined that serum OK reacts with both the 58-kd polypeptide and the 34-kd PCNA within complexes. Together with the results of a longitudinal analysis, these results suggest that the immune system of patient OK likely recognized the complexed PCNA protein, after which the autoimmune response spread to other elements of the complexes.Conclusion. Intermolecular-intrastructural help, leading to the spread of autoimmune response from PCNA to other proteins associated with its biologic function, plays a crucial role in the induction of the autoimmune response seen in lupus patients.Autoantibodies against proliferating cell nuclear antigen (PCNA) were first observed in a patient with systemic lupus erythematosus (SLE) (1). Using anti-PCNA antibodies from SLE patients as a probe, our group subsequently determined that PCNA is a 34-kd intranuclear polypeptide that exists mainly as a homotrimer (2,3), and that expression of PCNA is increased in the late G1 and early S phases of the cell cycle, immediately before DNA synthesis (4). These findings suggested an involvement of PCNA in DNA replication, and, indeed, PCNA was later identified as an auxiliary protein of DNA polymerase ␦ (Pol-␦), playing an essential role in DNA replication and repair (5-9).

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Section: Discussionmentioning

confidence: 99%

Autoimmune responses to proliferating cell nuclear antigen multiprotein complexes involved in cell proliferation are strongly associated with their structure and biologic function in patients with systemic lupus erythematosus

Kogure

Takasaki

Takeuchi

et al. 2002

Arthritis & Rheumatism

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“…Subsequently, PCNA was identified by Stillman and co-workers as a DNA elongation factor for SV40 DNA replication in vitro that increased the processivity of calf thymus DNA polymerase δ [14,15]. PCNA is a highly conserved eukaryotic homotrimeric protein that assembles around DNA to form a sliding clamp and acts as a processivity factor for the replicative polymerase (reviewed in [16]).…”

Section: Introductionmentioning

confidence: 99%

Physical and functional interaction of human nuclear uracil-DNA glycosylase with proliferating cell nuclear antigen

Bennett

2005

DNA Repair

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Uracil residues arise in DNA by the misincorporation of dUMP in place of dTMP during DNA replication or by the deamination of cytosine in DNA. Uracil-DNA glycosylase initiates DNA base excision repair of uracil residues by catalyzing the hydrolysis of the N-glycosylic bond linking the uracil base to deoxyribose. In human cells, the nuclear form of uracil-DNA glycosylase (UNG2) contains a conserved PCNA-binding motif located at the N-terminus that has been implicated experimentally in binding PCNA. Here we use purified preparations of UNG2 and PCNA to demonstrate that UNG2 physically associates with PCNA. UNG2 co-eluted with PCNA during size exclusion chromatography and bound to a PCNA affinity column. Association of UNG2 with PCNA was abolished by the addition of 100 mM NaCl, and significantly decreased in the presence of 10 mM MgCl 2 . The functional significance of the UNG2·PCNA association was demonstrated by UNG2 activity assays. Addition of PCNA (30-810 pmol) to standard uracil-DNA glycosylase reactions containing linear [uracil-3 H]DNA stimulated UNG2 catalytic activity up to 2.6-fold. UNG2 activity was also stimulated by 7.5 mM MgCl 2 . The stimulatory effect of PCNA was increased by the addition of MgCl 2 ; however, the dependence on PCNA concentration was the same, indicating that the effects of MgCl 2 and PCNA on UNG2 activity occurred by independent mechanisms. Loading of PCNA onto the DNA substrate was required for stimulation, as the activity of UNG2 on circular DNA substrates was not affected by the addition of PCNA. Addition of replication factor C and ATP to reactions containing 90 pmol of PCNA resulted in two-fold stimulation of UNG2 activity on circular DNA.

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“…PCNA has been shown to be an accessory protein for DNA polymerase 6 and is required for DNA replication and repair (Bravo et al, 1987;Prelich et al, 1987a,b;Prelich and Stillman, 1988;Toschi and Bravo, 1988;Bauer and Burgers, 1990;Shivji et al, 1992;Waseem et al, 1992 In this regard, PCNA or p21 may mediate the phosphorylation process of some of the replication factors during S-phase or DNA repair. However, there are indications suggesting that PCNA is not simply a replication factor.…”

Section: Glycerol Gradient Sedimentationmentioning

confidence: 99%

“…The p36 protein was identified as the proliferating cell nuclear antigen (PCNA), a protein previously shown to be involved in both DNA replication and repair (Bravo et al, 1987;Prelich et al, 1987a,b;Prelich and Stillman, 1988;Toschi and Bravo, 1988;Shivji et al, 1992). The identity of p21 is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes.

Zhang

Xiong

Beach

1993

MBoC

332

215

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We have recently shown that two proteins, proliferating cell nuclear antigen (PCNA) and p21, are associated with cyclin D. Here we show that PCNA and p21 are common components of a wide variety of cyclin/cyclin-dependent kinase complexes in nontransformed cells. These include kinase complexes containing cyclin A, cyclin B, and cyclin D, associated either with CDC2, CDK2, CDK4, or CDK5. We show that PCNA and p21 form separate quatemary complex with each cyclin/CDK and that these quatemary complexes contain a substantial, if not major, fraction of the cell cycle kinases in asynchronously growing cells. These results suggest that PCNA and p21 may perform a common function for all these kinases.

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The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro

Cited by 473 publications

References 38 publications

Autoimmune responses to proliferating cell nuclear antigen multiprotein complexes involved in cell proliferation are strongly associated with their structure and biologic function in patients with systemic lupus erythematosus

Autoimmune responses to proliferating cell nuclear antigen multiprotein complexes involved in cell proliferation are strongly associated with their structure and biologic function in patients with systemic lupus erythematosus

Physical and functional interaction of human nuclear uracil-DNA glycosylase with proliferating cell nuclear antigen

Proliferating cell nuclear antigen and p21 are components of multiple cell cycle kinase complexes.

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