Research Description
Recurrent chromosomal translocations are hallmarks of many hematopoietic cancers and solid tumors. Identification of the mechanistic factors that predispose to chromosomal translocations will provide important insights into cancer etiology as well as the prevention and therapy of cancers. Our previous works have demonstrated that formation of DNA double strand breaks (DSBs) and spatial organization of genome are critical for translocation initiation genome wide. However, much less is known about the mechanisms that lead to genome wide DSBs and subsequent processes that influence the probability of joining pairs of DSBs to form translocations. More importantly how those mechanistic factors contribute to cancer, especially in human patients, has not been carefully studied. We propose to employ and extend our high throughput genomic translocation sequencing (HTGTS) approach to characterize the potential and novel mechanistic factors. In addition, we will employ various genomic approaches to dissect the molecular mechanisms that lead to genomic instability during cancer initiation and development. Finally, we will extend the mechanistic studies to human cells and in vivo animal models.
· Understand how genome wide DSBs predisposed to chromosomal translocations are generated;
· Reveal the causal roles of mechanistic factors in regulating chromosomal translocations;
· Target the end-joining activities which mediate chromosomal translocations;
· Investigate the roles of mechanistic factors in human cancer development.