Publication Date:
2013-03-12
Description:
The regulated loading of the Mcm2-7 DNA helicase (comprising six related subunits, Mcm2 to Mcm7) into pre-replicative complexes at multiple replication origins ensures precise once per cell cycle replication in eukaryotic cells. The origin recognition complex (ORC), Cdc6 and Cdt1 load Mcm2-7 into a double hexamer bound around duplex DNA in an ATP-dependent reaction, but the molecular mechanism of this origin 'licensing' is still poorly understood. Here we show that both Mcm2-7 hexamers in Saccharomyces cerevisiae are recruited to origins by an essential, conserved carboxy-terminal domain of Mcm3 that interacts with and stimulates the ATPase activity of ORC-Cdc6. ATP hydrolysis can promote Mcm2-7 loading, but can also promote Mcm2-7 release if components are missing or if ORC has been inactivated by cyclin-dependent kinase phosphorylation. Our work provides new insights into how origins are licensed and reveals a novel ATPase-dependent mechanism contributing to precise once per cell cycle replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Frigola, Jordi -- Remus, Dirk -- Mehanna, Amina -- Diffley, John F X -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 Mar 21;495(7441):339-43. doi: 10.1038/nature11920. Epub 2013 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms EN6 3LD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23474987" target="_blank"〉PubMed〈/a〉
Keywords:
Adenosine Triphosphatases/*metabolism
;
Adenosine Triphosphate/metabolism
;
Amino Acid Sequence
;
Cell Cycle Proteins/metabolism
;
Chromosomal Proteins, Non-Histone/metabolism
;
DNA Replication/*genetics
;
DNA-Binding Proteins/metabolism
;
Enzyme Activation
;
Hydrolysis
;
Minichromosome Maintenance Complex Component 3
;
Minichromosome Maintenance Complex Component 7
;
Nuclear Proteins/metabolism
;
Protein Binding
;
Replication Origin/*genetics
;
Saccharomyces cerevisiae/cytology/enzymology/*genetics/*metabolism
;
Saccharomyces cerevisiae Proteins/metabolism
;
Sequence Alignment
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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