Tsai, Feng-Ling
(2012)
The Mcm2-7 Replicative Helicase is Essential to Coordinate DNA replication, Checkpoint Regulation and Sister Chromatid Cohesion.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
DNA replication is a complex and highly regulated cellular process that ensures faithful duplication of the entire genome. To prevent genomic instability, several additional processes are coordinated with DNA replication. Eukaryotic cells employ a conserved surveillance mechanism called the S-phase checkpoint to activate a phosphorylation cascade while encountering DNA damage during DNA replication. In addition, DNA replication must also coordinate with sister chromatid cohesion, so that sister DNAs emerged from the forks are physically connected until chromosomal segregation takes place. Mcm2-7, the eukaryotic replicative helicase that unwinds dsDNA and positions at the vanguard of the replication fork, is likely the commonality among these cellular processes. In my thesis work, I find that ATP hydrolysis in one specific active site (Mcm6/2) is required to mediate DNA replication checkpoint response, sister chromatid cohesion and DNA replication initiation. Further examination reveals that a subcircuit of the checkpoint pathway including MEC1 and MRC1 and ends with Mcm2-7 is required to mediate sister chromatid cohesion. Finally, misregulation of these processes causes genomic instability and likely missegregation of chromosomes. My findings lead to a model that the regulation of ATP hydrolysis at the Mcm6/2 active site by Mrc1 modulates Mcm2/5 gate open and gate closure during initiation, DNA damage and sister chromatid cohesion.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
5 July 2012 |
| Date Type: |
Publication |
| Defense Date: |
15 March 2012 |
| Approval Date: |
5 July 2012 |
| Submission Date: |
26 March 2012 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
167 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Biological Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
DNA replication
S-phase checkpoint
Sister chromatid cohesion
Mcm2-7 |
| Date Deposited: |
05 Jul 2012 16:42 |
| Last Modified: |
15 Nov 2016 13:56 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/11544 |
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