Crystal structure of the eukaryotic DNA polymerase processivity factor PCNA

Krishna, Talluru S.R.; Kong, Xiang‐Peng; Gary, Sonja L.; Burgers, Peter M.; Kuriyan, John

doi:10.1016/0092-8674(94)90014-0

Cited by 856 publications

(874 citation statements)

References 44 publications

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“…PCNA is fundamental to nuclear DNA replication, acting as a sliding clamp that tethers the leading strand DNA polymerase d to its template, enhancing the enzyme's processivity (Prelich et al, 1987;Bravo et al, 1987;Krishna et al, 1994). In addition, PCNA is required for nucleotide excision repair (Shivji et al, 1992;Nichols and Sancar, 1992) and is involved in one pathway of base excision repair (Matsumoto et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…This region corresponds to the central loop of PCNA between the two structurally conserved domains of each monomer, and includes the structural motifs bI1, bA2 and aA2 (from the crystal structure of S. cerevisiae PCNA, (Krishna et al, 1994). The central loop domain of PCNA provides a probable site for intermolecular interaction as it is highly exposed in native PCNA (Krishna et al, 1994). We show that p21 Cip1 has an identical pattern of binding to these PCNA deletion constructs ( Figure 6; , which is in contrast to the pattern of binding by Gadd45 .…”

Section: Evolutionary Conservation Of the Fen1-pcna Interactionmentioning

confidence: 99%

“…Figure 6 Two hybrid analysis of Fen1 and p21 Cip1 binding to PCNA. An entire PCNA monomer is shown schematically, with structural domains designated as described by Krishna et al (1994). A series of N terminal and C terminal deletions of PCNA was constructed in frame with the DNA binding domain of Gal4, and expressed in the two hybrid system with Fen1 expressed as a fusion protein with the transcriptional activation domain of Gal4.…”

Section: Evolutionary Conservation Of the Fen1-pcna Interactionmentioning

confidence: 99%

“…Proliferating cell nuclear antigen is essential for DNA replication, acting as the processivity factor for DNA polymerases d and e. As a homotrimer, PCNA forms a toroidal structure capable of interacting nonspeci®cally with double stranded DNA by encircling it, and thus forming a sliding clamp which tethers the polymerase to the DNA strand (Krishna et al, 1994; reviewed by Kuriyan and O'Donnell, 1993). PCNA is highly conserved and has been identi®ed as an essential gene required for DNA replication in the yeasts Schizosaccharomyces pombe (Waseem et al, 1992) and Saccharomyces cerevisiae (Bauer and Burger, 1990).…”

Section: Introductionmentioning

confidence: 99%

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Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair

et al. 1997

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Following genomic damage, the cessation of DNA replication is co-ordinated with onset of DNA repair; this co-ordination is essential to avoid mutation and genomic instability. To investigate these phenomena, we have analysed proteins that interact with PCNA, which is required for both DNA replication and repair. One such protein is p21 Cip1 , which inhibits DNA replication through its interaction with PCNA, while allowing repair to continue. We have identi®ed an interaction between PCNA and the structure speci®c nuclease, Fen1, which is involved in DNA replication. Deletion analysis suggests that p21 Cip1 and Fen1 bind to the same region of PCNA. Within Fen1 and its homologues a small region (10 amino acids) is su cient for PCNA binding, which contains an 8 amino acid conserved PCNA-binding motif. This motif shares critical residues with the PCNA-binding region of p21 Cip1 . A PCNA binding peptide from p21 Cip1 competes with Fen1 peptides for binding to PCNA, disrupts the Fen1-PCNA complex in replicating cell extracts, and concomitantly inhibits DNA synthesis. Competition between homologous regions of Fen1 and p21 Cip1 for binding to the same site on PCNA may provide a mechanism to co-ordinate the functions of PCNA in DNA replication and repair.

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Section: Discussionmentioning

confidence: 99%

Section: Evolutionary Conservation Of the Fen1-pcna Interactionmentioning

confidence: 99%

Section: Evolutionary Conservation Of the Fen1-pcna Interactionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair

et al. 1997

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“…4C, lanes 7–12). The ring‐shaped structure of PCNA and the IDCL is conserved among PCNAs from H. sapiens , Saccharomyces cerevisiae , and E. histolytica 3, 4. As the role of PCNA in the catalytic enhancement of the nick‐sealing step by DNA ligases is controversial 16, 21, we tested if an orthologous PCNA from H. sapiens would influence the nick‐sealing activity of EhDNAligI.…”

Section: Resultsmentioning

confidence: 99%

Proliferating cell nuclear antigen restores the enzymatic activity of a DNA ligase I deficient in DNA binding

Trasviña-Arenas¹,

Cardona-Félix²,

Azuara-Licéaga

et al. 2017

FEBS Open Bio

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Proliferating cell nuclear antigen (PCNA) coordinates multienzymatic reactions by interacting with a variety of protein partners. Family I DNA ligases are multidomain proteins involved in sealing of DNA nicks during Okazaki fragment maturation and DNA repair. The interaction of DNA ligases with the interdomain connector loop (IDCL) of PCNA through its PCNA‐interacting peptide (PIP box) is well studied but the role of the interacting surface between both proteins is not well characterized. In this work, we used a minimal DNA ligase I and two N‐terminal deletions to establish that DNA binding and nick‐sealing stimulation of DNA ligase I by PCNA are not solely dependent on the PIP box–IDCL interaction. We found that a truncated DNA ligase I with a deleted PIP box is stimulated by PCNA. Furthermore, the activity of a DNA ligase defective in DNA binding is rescued upon PCNA addition. As the rate constants for single‐turnover ligation for the full‐length and truncated DNA ligases are not affected by PCNA, our data suggest that PCNA stimulation is achieved by increasing the affinity for nicked DNA substrate and not by increasing catalytic efficiency. Surprisingly C‐terminal mutants of PCNA are not able to stimulate nick‐sealing activity of Entamoeba histolytica DNA ligase I. Our data support the notion that the C‐terminal region of PCNA may be involved in promoting an allosteric transition in E. histolytica DNA ligase I from a spread‐shaped to a ring‐shaped structure. This study suggests that the ring‐shaped PCNA is a binding platform able to stabilize coevolved protein–protein interactions, in this case an interaction with DNA ligase I.

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Temporal and histologic relationships of proliferating cell nuclear antigen and human papillomavirus type 11 in the mouse xenograft system

et al. 1996

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Proliferating cell nuclear antigen (PCNA) is an accessory protein of DNA polymerase delta. This protein is associated with cell cycle progression and can be detected in the replicating cells of normal tissues. Condylomata acuminata are benign epithelial tumors caused by infection with human papillomaviruses and are characterized by abnormal cell proliferation. The athymic mouse xenograft model of HPV 11 infection was used to test the hypothesis that PCNA is induced early in the course of HPV 11 infection and to study the temporal and histologic relationships between detection of PCNA and HPV DNA. Human foreskin tissue was infected with HPV 11 and implanted under the renal capsules of 10 athymic mice. Pairs of mice were sacrificed every week beginning four weeks after implantation. HPV DNA was detected in sections of foreskin implants by in situ hybridization. PCNA was as or more abundant in implants removed at earlier time points than at later time points, whereas HPV DNA became increasingly more abundant with time. PCNA was detected only in basal cells in areas of histologically normal epithelium that were also negative for HPV DNA. In contrast, PCNA was present throughout the epithelium in regions that were HPV DNA-positive. HPV DNA was detected only in differentiated epithelial cells in implants removed at all five time points, but in HPV DNA-positive regions, PCNA was detected with equal intensity in differentiated and undifferentiated cells. The foci of PCNA-positive cells were well demarcated and were larger than, but included, the foci of HPV DNA-positive cells. PCNA may be induced maximally in differentiated epithelium by HPV 11 prior to significant HPV DNA replication.

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Crystal structure of the eukaryotic DNA polymerase processivity factor PCNA

Cited by 856 publications

References 44 publications

Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair

Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair

Proliferating cell nuclear antigen restores the enzymatic activity of a DNA ligase I deficient in DNA binding

Temporal and histologic relationships of proliferating cell nuclear antigen and human papillomavirus type 11 in the mouse xenograft system

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