Understanding the mechanism of inheritance of chromosomes in human cells is a fundamental problem inbiology and has direct relevance to cancer research. Alterations to the normal pattern of inheritancepromote progression to cancer by the accumulation of somatic genetic aberrations in the genome of tumorcells. The regulatory pathways investigated by others in this Program Project directly control the DNAreplication and mitosis. The proposed studies focus how a cell duplicates and segregates chromosomes andare based on the observation that Origin Recognition Complex (ORC) in human cells participates in many ofthese processes. ORC is required for the initiation of DNA replication and recent research has demonstratedthat ORC, or ORC subunits participate in other aspects of chromosome inheritance and cell division.
The first aim will address the dynamic assembly of ORC during the cell division cycle and determine how thisprocess is regulated.
A second aim will identify and characterize ORC associated proteins in chromosomeinheritance, suing both proteomic methods (with Core D) and genetic approaches with an RNAi library (CoreB) to discover cellular proteins essential for Epstein Barr Virus replication.
A third aim will expand researchon the role of ORC in maintenance of heterochromatin and a potential relationship with the RNAi machinerymaintaining heterochromatin.
A final aim will study the role of ORC subunits in centrosomes duplication andcontrol chromosome segregation. Although the cell division cycle regulatory machinery coordinates themultiple stages of the chromosome inheritance cycle, research in this Project suggests a more fundamentalconnection between the actual processes of DNA replication and chromosome segregation. Thus thesestudies on chromosome inheritance are directly relevant to the overall goals of the program project and theother projects in the Program.
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