This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Transcriptional gene silencing is brought about by the formation of heterochromatin at specific chromosomal loci. Important chromosomal substructures such as the centromere depend on heterochromatin and play a crucial role in genome stability, cell division and regulation of gene expression. Consequently, uncontrolled formation and maintenance of heterochromatin are closely linked to diseases such as cancer and developmental disorders. It has been quite surprising to find that centromeres are established and maintained by a pathway closely linked to RNA interference (RNAi). In Schizosaccharomyces pombe three major protein complexes have been identified which are RITS - the siRNA carrying effector complex - an RNA dependent RNA polymerase complex (RDRC) as well as protein complexes based on the protein Rik1. My research will focus on the functional and structural characterization of RITS and Rik1. Production of the target complexes will be approached by recombinant heterologuous expression in the Baculo virus expression system with subsequent structural and functional investigation of the complexes aimed at elucidating their role in the process of RNAi mediated transcriptional gene silencing. Expression of protein complexes in eukaryotic cell cultures and challenging functional as well as high resolution structural analysis will favourably add to my previous experience in low resolution structural work. With this fellowship, I will get an excellent opportunity to develop my career towards an independent researcher in the very stimulating and highly interdisciplinary environment of the Cold Spring Harbor Laboratories.
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