5 U01 U01HG04279
The Systematic Identification and Analysis of Replicatio
| Principal Investigator: |
David MacAlpine
Dept of Pharm and Cancer Biol.
Lev Sci Res Ctr
Box 3813 Med Ctr
|
Project Period: 05/04/2007 - 03/31/2011
Abstract (from grant application):
DESCRIPTION: DNA replication is an essential cell cycle process required to duplicate the chromosomes each and every cell division. Very little is known about how replication is coordinated with other nuclear processes such as transcription and chromatin modification. Although recent genomic studies have demonstrated a correlation between time of DNA replication and transcriptional activity, with actively transcribed regions of the genome being replicated early, the underlying mechanism driving this correlation remains unclear. Only by systematically characterizing the replication dynamics of a metazoan genome in multiple cell types will we be in a position to understand the mechanisms by which these processes are coordinated to maintain genomic stability. We will use high-density genomic tiling-path arrays to characterize fully the Drosophila replication program in multiple cell lines and tissues. Specifically, we will determine the time of replication for all unique sequences in Drosophila genome, identify and map all functional origins of replication, and identify all sites of prereplicative complex (preRC, an essential multi-protein complex required for replication initiation) assembly. The high-resolution mapping of sites of preRC assembly will enable us to apply computational approaches (including comparative genomics) to identify potential sequence motifs that direct and regulate preRC function. Finally, we will also characterize the differential replication of polytene chromosomes in fully differentiated Drosophila tissues to identify genomic regions that are amplified or underreplicated. The differential replication of polytene chromosomes provides a unique opportunity to understand how developmental cues and chromosomal domains influence the replication program. In proliferating cells, duplication of the genome is a critical cell-cycle event, not only must the genome be copied accurately; it must also be copied exactly once. The regulation of origin selection and activation is essential to maintain genomic stability. The failure to completely replicate the genome or the inappropriate over-replication of select sequences may lead to tumorigenesis.
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