Authors
Patel, Prasanta K.Kommajosyula, Naveen
Rosebrock, Adam
Bensimon, Aaron
Leatherwood, Janet K.
Bechhoefer, John
Rhind, Nicholas R.
UMass Chan Affiliations
Program in Molecular MedicineDepartment of Biochemistry and Molecular Pharmacology
Graduate School of Biomedical Sciences
Document Type
Journal ArticlePublication Date
2008-09-19
Metadata
Show full item recordAbstract
Origins of DNA replication are generally inefficient, with most firing in fewer than half of cell cycles. However, neither the mechanism nor the importance of the regulation of origin efficiency is clear. In fission yeast, origin firing is stochastic, leading us to hypothesize that origin inefficiency and stochasticity are the result of a diffusible, rate-limiting activator. We show that the Hsk1-Dfp1 replication kinase (the fission yeast Cdc7-Dbf4 homologue) plays such a role. Increasing or decreasing Hsk1-Dfp1 levels correspondingly increases or decreases origin efficiency. Furthermore, tethering Hsk1-Dfp1 near an origin increases the efficiency of that origin, suggesting that the effective local concentration of Hsk1-Dfp1 regulates origin firing. Using photobleaching, we show that Hsk1-Dfp1 is freely diffusible in the nucleus. These results support a model in which the accessibility of replication origins to Hsk1-Dfp1 regulates origin efficiency and provides a potential mechanistic link between chromatin structure and replication timing. By manipulating Hsk1-Dfp1 levels, we show that increasing or decreasing origin firing rates leads to an increase in genomic instability, demonstrating the biological importance of appropriate origin efficiency.Source
Mol Biol Cell. 2008 Dec;19(12):5550-8. Epub 2008 Sep 17. Link to article on publisher's siteDOI
10.1091/mbc.E08-06-0645Permanent Link to this Item
http://hdl.handle.net/20.500.14038/32801PubMed ID
18799612Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1091/mbc.E08-06-0645