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The Mcm2-7 Replicative Helicase is Essential to Coordinate DNA replication, Checkpoint Regulation and Sister Chromatid Cohesion

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 (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSchwacha, Anthonyschwacha@pitt.eduSCHWACHA
Committee MemberArndt, Karenarndt@pitt.eduARNDT
Committee MemberHendrix, Rogerrhx@pitt.eduRHX
Committee MemberVanDemark, Andrewandyv@pitt.eduANDYV
Committee MemberWoolford, John,
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


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