EXCEED THE SPACE PROVIDED. In metazoans, sites at which DNA replication initiates do not appear to be determined by the location of DNA specific sequences distributed along the genome. Rather, where initiation sites assemble appears to be largely determined by chromatin modification. It is likely that some modifications facilitate the establishment of initiation sites while others block the formation of such sites. We are interested in distinguishing between these types of modifications and in understanding how such modifications are successfully passed on and inherited by DNA during cell division. Towards this goal we propose to examine the mechanisms that regulate how ORC and cdc6 interact with DNA to form PRC's and to determine how certain chromatin modifications, such as DNA Methylation, and acetylation, inhibits PRC formation. We will also investigate how these proteins load the MCM Helicase onto DNA and determine how this Helicase functions during the initiationof DNA replication. With respect to how ORC may be targeted to specific chromatin domains we will investigate how the ribosomal DNA binding factor UBF, interacts with ORC and whether this interaction targets ORC to bind to specific chromatin modifications. Lastly, we will investigate how chromatin modifications are stably inherited by investigating how the H3-1ike protein Cenp A is assembled and inherited at kinetochores. Together, the results of these studies should provide information both about how initiation of replication is established and maintained in metazoans and how such information is inherited during cell division. PERFORMANCE SITE ========================================Section End===========================================
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