How a DNA Polymerase Clamp Loader Opens a Sliding Clamp

Kelch, Brian A.; Makino, Debora L.; O’Donnell, Michael; Kuriyan, John

doi:10.1126/science.1211884

Cited by 160 publications

(400 citation statements)

References 61 publications

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“…Host and viral DNA replication is contingent on rapid and processive DNA synthesis. DNA polymerase tethering to the PCNA sliding clamp permits processive replication (29). PCNA is a closed circle and requires RFC enzymatic activity to load onto and encircle DNA.…”

Section: Discussionmentioning

confidence: 99%

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Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

Sun

Tsurimoto

Juillard

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Kaposi's sarcoma herpesvirus (KSHV) latently infects tumor cells, and viral episomal DNA replicates once each cell cycle. KSHV does not express DNA replication proteins during latency. Instead, KSHV latency-associated nuclear antigen (LANA) recruits host cell DNA replication machinery to the replication origin. However, the mechanism by which LANA mediates replication is uncertain. Here, we show LANA recruits replication factor C, the DNA polymerase clamp [proliferating cell nuclear antigen (PCNA)] loader, in a critical step for viral DNA replication. Our findings suggest that PCNA loading is a rate-limiting step in DNA replication that is incompatible with KSHV persistence. LANA-enhanced PCNA loading is necessary for virus replication and persistent infection. These data reveal a therapeutic target for inhibition of KSHV persistence in malignant cells.

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Section: Discussionmentioning

confidence: 99%

“…PCNA is a closed circle and requires RFC enzymatic activity to load onto and encircle DNA. RFC, an AAA+ clamp-loading ATPase, consists of five subunits (RFC1-RFC5) (26,29,30). In alternative RFC complexes, other subunits substitute for RFC1 to function in specialized pathways, such as for DNA damage (26).…”

Section: Discussionmentioning

confidence: 99%

Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

Sun

Tsurimoto

Juillard

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…A recent structural study with the T4 bacteriophage clamp loader suggested that hydrolysis of one ATP molecule causes a conformational change in the clamp loader⅐clamp complex that closes the clamp (30), and studies with the E. coli replisome suggest that hydrolysis of one ATP molecule is sufficient to form initiation complexes but hydrolysis of 3 molecules accelerates the process (31,32). Studies have shown that ATP hydrolysis is required for clamp release (24,26,33), but the question here is whether ATP hydrolysis is required for clamp closing or whether binding of the clamp loader⅐clamp complex to DNA is sufficient to promote clamp closing.…”

mentioning

confidence: 99%

The β Sliding Clamp Closes around DNA prior to Release by the Escherichia coli Clamp Loader γ Complex

Hayner

Bloom

2013

Journal of Biological Chemistry

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Background:The ␥ complex loads the ring-shaped ␤ sliding clamp onto DNA. Results: The rate of ␤ clamp closing is faster than the rate of ␤ release on DNA, and the first turnover of ATP hydrolysis is faster than ␤ closing. Conclusion: Clamp closing occurs before clamp release but after a burst of ATP hydrolysis.Significance: These results demonstrate that clamp release around DNA is a two-step process.

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“…The primase requires contact with single-stranded DNA-binding protein (SSB) (14) to remain bound to the RNA primer. Disruption of this interaction mediated by the polymerase clamp loader leads to primase displacement (14); β-clamp loading on primed DNA (15,16); and, finally, interaction of the polymerase core subunits with the β-clamp-loaded template (14,17). β-clamp loading is a complex reaction involving clamp opening and then positioning around the DNA with the use of the clamp loader (reviewed in ref.…”

mentioning

confidence: 99%

Plasmid replication initiator interactions with origin 13-mers and polymerase subunits contribute to strand-specific replisome assembly

Wawrzycka

Gross

Wasaznik

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although the molecular basis for replisome activity has been extensively investigated, it is not clear what the exact mechanism for de novo assembly of the replication complex at the replication origin is, or how the directionality of replication is determined. Here, using the plasmid RK2 replicon, we analyze the protein interactions required for Escherichia coli polymerase III (Pol III) holoenzyme association at the replication origin. Our investigations revealed that in E. coli, replisome formation at the plasmid origin involves interactions of the RK2 plasmid replication initiation protein (TrfA) with both the polymerase β-and α-subunits. In the presence of other replication proteins, including DnaA, helicase, primase and the clamp loader, TrfA interaction with the β-clamp contributes to the formation of the β-clamp nucleoprotein complex on origin DNA. By reconstituting in vitro the replication reaction on ssDNA templates, we demonstrate that TrfA interaction with the β-clamp and sequence-specific TrfA interaction with one strand of the plasmid origin DNA unwinding element (DUE) contribute to strand-specific replisome assembly. Wild-type TrfA, but not the TrfA QLSLF mutant (which does not interact with the β-clamp), in the presence of primase, helicase, Pol III core, clamp loader, and β-clamp initiates DNA synthesis on ssDNA template containing 13-mers of the bottom strand, but not the top strand, of DUE. Results presented in this work uncovered requirements for anchoring polymerase at the plasmid replication origin and bring insights of how the directionality of DNA replication is determined.DNA replication initiation | polymerase III | β-clamp | Rep | plasmid RK2

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How a DNA Polymerase Clamp Loader Opens a Sliding Clamp

Cited by 160 publications

References 61 publications

Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

Kaposi's sarcoma-associated herpesvirus LANA recruits the DNA polymerase clamp loader to mediate efficient replication and virus persistence

The β Sliding Clamp Closes around DNA prior to Release by the Escherichia coli Clamp Loader γ Complex

Plasmid replication initiator interactions with origin 13-mers and polymerase subunits contribute to strand-specific replisome assembly

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