"Chromosomal fragile sites (CFS) are naturally occurring hot-spots for DNA breakage. CFS are frequent breakpoints for chromosome translocations, prone to expansion of repetitive elements and susceptible to other types of genetic instability. Chromosomal fragile sites have therefore been linked to several types of cancer as well as to neurological disorders such as obsessive-compulsive disorder, type I bipolar disorder, schizophrenia and Fragile X syndrome. In most cases, CFS are cytogenetically defined megabase regions of the genome and the underlying molecular mechanisms and genetic requirements for fragile site instability are unknown. This is largely due to the difficulty of genetic manipulation of these elements in human cells. In order to investigate the molecular mechanisms and genetic requirements that control fragile site stability, we will take advantage of two genetic model systems, the yeast Saccharomyces cerevisiae and the vertebrate DT40 cell line (Gallus gallus), which allow for genome-wide screens and genetic manipulation to test specific hypotheses regarding chromosomal fragile sites.The goal of this project is to perform a molecular, genetic and cell biological analysis of CFS. Specifically, the aims of this project are (i) to identify the genetic requirements for fragile site expression (ii) to isolate and characterize proteins that bind to fragile sites and (iii) to investigate the impact of transcription, replication and chromatin structure on fragile site expression."
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