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Novel “ Checkpoint ” Mechanism Mediates DNA Damage Responses

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Experiments by Philip Hanawalt and his student David Pettijohn at Stanford University in 1963 suggested that the molecular machinery of DNA replication and repair—which they discovered at sites of damage—are quite similar and closely linked... While many studies have since supported that link, Viola Ellison and Bruce Stillman, the director of the Cold Spring Harbor Laboratory, have found new evidence that the two processes may indeed coincide by showing that protein complexes regulating a cellular checkpoint in DNA repair operate much like similar complexes involved in DNA replication... Two protein complexes required for this process are replication factor C (RFC) and proliferating cell nuclear antigen (PCNA)... In the 1980s, Stillman's laboratory isolated PCNA and RFC and showed that they function together to “load” PCNA onto a structure in DNA that is created after DNA synthesis begins... A subset of these proteins, which are conserved in human cells, form two protein complexes—RSR and RHR—that function like RFC and PCNA, respectively, with RSR loading the RHR clamp onto DNA... Ellison and Stillman demonstrate that both pairs of “clamp-loading” complexes follow similar biochemical steps, but, significantly, RFC and RSR favor different DNA structures for clamp loading... The discovery that RSR loads its RHR clamp onto a different DNA structure was unexpected; it suggests not only that the two clamp loaders have distinct replication and repair functions, but also how the checkpoint machinery might work to prevent DNA damage from being passed on to future generations... By establishing the chemical requirements of RSR/RHR interactions as well as the preferred DNA-binding substrate, the researchers have charted the way for determining the different functions of these cell cycle checkpoint complexes and how the complexes' different subunits affect these functions... The researchers propose that the role of this checkpoint machinery is not as an initial sensor of DNA damage, but rather as a facilitator of DNA repair, stepping in after preliminary repairs to DNA lesions have been made... Ellison and Stillman's work helps establish a biochemical model for studying how both of these checkpoint complexes function to coordinate replication and repair—and promise to help scientists understand how cancer develops when the checkpoint repair mechanisms fail.

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Possible targets for the RHR checkpoint clamp
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pbio.0000054-g001: Possible targets for the RHR checkpoint clamp


Novel “ Checkpoint ” Mechanism Mediates DNA Damage Responses
Possible targets for the RHR checkpoint clamp
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC261891&req=5

pbio.0000054-g001: Possible targets for the RHR checkpoint clamp

View Article: PubMed Central

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Experiments by Philip Hanawalt and his student David Pettijohn at Stanford University in 1963 suggested that the molecular machinery of DNA replication and repair—which they discovered at sites of damage—are quite similar and closely linked... While many studies have since supported that link, Viola Ellison and Bruce Stillman, the director of the Cold Spring Harbor Laboratory, have found new evidence that the two processes may indeed coincide by showing that protein complexes regulating a cellular checkpoint in DNA repair operate much like similar complexes involved in DNA replication... Two protein complexes required for this process are replication factor C (RFC) and proliferating cell nuclear antigen (PCNA)... In the 1980s, Stillman's laboratory isolated PCNA and RFC and showed that they function together to “load” PCNA onto a structure in DNA that is created after DNA synthesis begins... A subset of these proteins, which are conserved in human cells, form two protein complexes—RSR and RHR—that function like RFC and PCNA, respectively, with RSR loading the RHR clamp onto DNA... Ellison and Stillman demonstrate that both pairs of “clamp-loading” complexes follow similar biochemical steps, but, significantly, RFC and RSR favor different DNA structures for clamp loading... The discovery that RSR loads its RHR clamp onto a different DNA structure was unexpected; it suggests not only that the two clamp loaders have distinct replication and repair functions, but also how the checkpoint machinery might work to prevent DNA damage from being passed on to future generations... By establishing the chemical requirements of RSR/RHR interactions as well as the preferred DNA-binding substrate, the researchers have charted the way for determining the different functions of these cell cycle checkpoint complexes and how the complexes' different subunits affect these functions... The researchers propose that the role of this checkpoint machinery is not as an initial sensor of DNA damage, but rather as a facilitator of DNA repair, stepping in after preliminary repairs to DNA lesions have been made... Ellison and Stillman's work helps establish a biochemical model for studying how both of these checkpoint complexes function to coordinate replication and repair—and promise to help scientists understand how cancer develops when the checkpoint repair mechanisms fail.

No MeSH data available.