Cancer Center Member
Erik J Sontheimer, PhD
Professor, Molecular Biosciences; Judd A. and Marjorie Weinberg College of Arts and Sciences
Cancer Cell Biology
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Cancer Focused Research:
RNA molecules are essential participants in many aspects of cellular function. We aim to understand the roles and mechanisms of regulatory RNAs in gene expression, with an emphasis on genetic interference pathways. Although these pathways [in particular, RNA interference (RNAi)] were reported in eukaryotes more than a decade ago, analogous RNA-guided silencing phenomena were thought to be largely absent in bacteria and archaea. In 2007, however, genetic elements known as clustered, regularly interspaced, short palindromic repeat (CRISPR) loci were revealed as sequence-based specificity determinants of an RNA-guided adaptive immune system that defends against virus infection. Although this pathway has functional parallels with RNAi in eukaryotes, the mechanisms of RNAi and CRISPR interference are completely distinct. We are working to understand the roles and mechanisms of CRISPR interference in bacteria. We have already shown that the CRISPR RNAs (crRNAs) that specify interference can target DNA rather than RNA, establishing a fundamental distinction between CRISPR interference and RNAi. We are now employing biochemical approaches to identify the molecular events that lead to crRNA-directed silencing.
Another research avenue is an analysis of the roles of non-coding RNAs (ncRNAs), as well as non-coding portions of mRNAs, in the budding yeast Saccharomyces cerevisiae. Unlike most other eukaryotes, this model organism lacks the signature components of the RNAi machinery, indicating that it uses other RNA-based systems to regulate gene expression. Our genome-wide analyses of RNAs expressed during meiosis and sporulation has revealed large numbers of ncRNAs, as well as an unanticipated degree of dynamism in transcript architecture. We are now using this dataset as a springboard to identify and characterize novel modes of eukaryotic gene regulation.