The many faces of redundancy in DNA replication control
Abstract
The large genomes of eukaryotic cells are replicated from multiple replication origins during S phase of the cell cycle. These origins are not activated synchronously at the beginning of S phase but, instead, fire throughout S phase according to a predetermined, cell-type-specific program. Ensuring that each origin is efficiently activated once and only once during each S phase is crucial for maintaining the integrity of the genome. This is achieved by a two-step mechanism. The first step, licensing, involves the loading of the Mcm2-7 proteins into pre-replicative complexes (pre-RCs) at origins by ORC, Cdc6, and Cdt1. Pre-RCs can only assemble at origins during G(1) phase, when cyclin-dependent kinase (CDK) activity is low because CDKs inhibit each pre-RC component individually. CDKs trigger initiation by phosphorylating two essential proteins, Sld2 and Sld3. A second protein kinase, Cdc7, along with its regulatory subunit, Dbf4, is also required for initiation. In response to DNA damage, origin firing is inhibited by a third protein kinase, Rad53, which phosphorylates and inhibits Sld3 and Dbf4. In this chapter, I describe these regulatory mechanisms in detail and explore the role of redundancy in the regulation of DNA replication, focusing on the budding yeast, Saccharomyces cerevisiae.
Journal details
Volume 75
Pages 135-142
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Publisher website (DOI) 10.1101/sqb.2010.75.062
Europe PubMed Central 21502406
Pubmed 21502406
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