2007 Fiscal Year Final Research Report Summary
Roles of fork protection complex and cdc7 kinase in fork-stabilization and replication checkpoint
| Project/Area Number |
18570169
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Molecular biology
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| Research Institution | Tokyo Metropolitan Organization for Medical Research |
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Principal Investigator |
YOSHIZAWA Naoko (須賀田 直子) Tokyo Metropolitan Organization for Medical Research, Tokyo Metropolitan Institute of Medical Science, Researcher (30344071)
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| Project Period (FY) |
2006 – 2007
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| Keywords | replication fork / replication checkpoint / fork protection complex / Cdc7 / DNA damage / recombinational repair / chromosome cohesion / DNA replication |
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| Research Abstract |
Coordinated execution of DNA replication, checkpoint activation and post-replicative chromatid cohesion is intimately related to the replication fork machinery. In this study, we focused on the human homologs of replication complex components, AND-1, Tim, and Tipin and identified their functions in S phase as below.
1. Human Tim and Tipin form complex during cell cycle. Coimmunoprecipitation experiments reveals that Tim also interacts with Mcm2 and AND-1 interacts with cohesin Smc1, Smc3 Rad21 and Mcm7.
2. AND-1, Tim and Tipin localize adjacent to replication foci and are required for efficient DNA replication.
3. Depletion of AND-1 causes DNA damage and cell death.
4. AND-1, Tim and Tipin are required for efficient replication checkpoint and promote UV-resistant DNA replication. Tim and Tipin are also required for chromatin loading of Claspin in replication stress.
5. AND-1 is phosphorylated by replication arrest which depends on ATM/ATR and Cdc7 kinase.
6. AND-1 is required for efficient recombinational repair.
Based on these data, we propose that AND- 1, Tim and Tipin forms complexes with cohesin and replication factors and coordinates multiple cellular events in S phase, such as DNA replication, checkpoint activation, sister chromatid cohesion and repair, thus playing a pivotal role in maintenance of genome integrity.
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