2026-09-19T07:25:11Zhttps://dspace.mit.edu/server/oai/requestoai:dspace.mit.edu:1721.1/372592022-01-13T07:54:15Zcom_1721.1_7582com_1721.1_7581col_1721.1_131022
Stephen P. Bell.
Tanny, Robyn E
Massachusetts Institute of Technology. Dept. of Biology.
Massachusetts Institute of Technology. Department of Biology
2007-04-20T15:57:45Z
2007-04-20T15:57:45Z
2006
2006
http://hdl.handle.net/1721.1/37259
85844539
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2006.
Includes bibliographical references.
Every time a cell divides it must faithfully duplicate its genome before the cell divides. If replication initiates a second time (re-replication) before cytokinesis, cells can accumulate extensive DNA damage, which results in genomic instability, a hallmark of tumorigenesis. To prevent re-replication eukaryotic cells must inhibit the re-initiation of replication start sites, or origins, across the genome. Examples of both Cyclin-Dependent Kinase (CDK)-dependent and CDK-independent mechanisms have been identified that regulate the components of the pre-Replicative Complex (pre-RC) to prevent re-replication. The pre-RC is a multi-protein complex that assembles at origins during G1, before DNA replication begins. After an origin initiates pre-RC components must be prevented from reassembling at origins until the next cell cycle. When the mechanisms preventing re-replication in the yeast Saccharomyces cerevisiae are disrupted, unregulated replication occurs. Not all origins are capable of re-initiating during this re-replication. Rather, a subset of all potential origin sequences reform pre-RCs, and of those, only a portion re-initiates. The origins that re-initiate do not correlate with any other known subclass of origins (e.g. - early/late initiating origins).
(cont.) The inability of some origins to form pre-RCs during re-replication might be due to restrictive chromatin structure preventing pre-RC components from associating with origin DNA. Similarly, origins that form pre-RCs but do not re-initiate might be prevented from recruiting replication machinery due to a restrictive chromatin structure. In addition, these origins might not re-initiate because replication factors that function downstream of pre-RC components also could be regulated to prevent re-replication. One of the mechanisms that S. cerevisiae and other eukaryotes use to prevent re-replication is phosphorylating one or multiple subunits of the Origin Recognition Complex (ORC). In S. cerevisiae, Orc2 and Orc6 are both phosphorylated but have distinct mechanisms for preventing re-replication. Phosphorylating Orc2 results in the direct inhibition of pre-RC assembly whereas phosphorylating Orc6 helps stabilize CDK at origins. By contrast, of CDK helps to prevent re-replication, most likely through a combination of catalytic activity and steric hindrance.
by Robyn E. Tanny.
Ph.D.
161 leaves
eng
Massachusetts Institute of Technology
M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.
http://dspace.mit.edu/handle/1721.1/7582
Biology.
Mechanisms that prevent DNA re-replication in the yeast Saccharomyces cerevisiae
Mechanisms that prevent deoxyribonucleic acid re-replication in the yeast S. cerevisiae
Thesis
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<Abstract>Every time a cell divides it must faithfully duplicate its genome before the cell divides. If replication initiates a second time (re-replication) before cytokinesis, cells can accumulate extensive DNA damage, which results in genomic instability, a hallmark of tumorigenesis. To prevent re-replication eukaryotic cells must inhibit the re-initiation of replication start sites, or origins, across the genome. Examples of both Cyclin-Dependent Kinase (CDK)-dependent and CDK-independent mechanisms have been identified that regulate the components of the pre-Replicative Complex (pre-RC) to prevent re-replication. The pre-RC is a multi-protein complex that assembles at origins during G1, before DNA replication begins. After an origin initiates pre-RC components must be prevented from reassembling at origins until the next cell cycle. When the mechanisms preventing re-replication in the yeast Saccharomyces cerevisiae are disrupted, unregulated replication occurs. Not all origins are capable of re-initiating during this re-replication. Rather, a subset of all potential origin sequences reform pre-RCs, and of those, only a portion re-initiates. The origins that re-initiate do not correlate with any other known subclass of origins (e.g. - early/late initiating origins).</Abstract>
<Abstract>(cont.) The inability of some origins to form pre-RCs during re-replication might be due to restrictive chromatin structure preventing pre-RC components from associating with origin DNA. Similarly, origins that form pre-RCs but do not re-initiate might be prevented from recruiting replication machinery due to a restrictive chromatin structure. In addition, these origins might not re-initiate because replication factors that function downstream of pre-RC components also could be regulated to prevent re-replication. One of the mechanisms that S. cerevisiae and other eukaryotes use to prevent re-replication is phosphorylating one or multiple subunits of the Origin Recognition Complex (ORC). In S. cerevisiae, Orc2 and Orc6 are both phosphorylated but have distinct mechanisms for preventing re-replication. Phosphorylating Orc2 results in the direct inhibition of pre-RC assembly whereas phosphorylating Orc6 helps stabilize CDK at origins. By contrast, of CDK helps to prevent re-replication, most likely through a combination of catalytic activity and steric hindrance.</Abstract>
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