Sunday, November 24, 2024
11/24/2024
Summary Silencing of transposable and repetitive elements maintains genome integrity, and defects in silencing pathways lead to cancer formation. Despite the importance, little is known how transposable and repetitive elements are initially recognized and targeted for silencing and how they regulate important biological processes. To address this knowledge gap, we will combine genetics and molecular biology with biochemistry and cryo-EM. Genomes are under constant threat of invasion by transposable elements and other genomic parasites. These foreign genomic elements will use the host for their own expression and proliferation. Silencing of existing transposable and repetitive elements has been well studied, however, little is known how new transposable elements are recognized. Although most of the repetitive genome consist of transposable and other foreign elements, repeats of ribosomal DNA (rDNA) form a unique type of a repetitive genome, in which some repeats are silenced while others are highly expressed. rDNA is localized in the nucleolus, a special compartment that is considered to be phase separated by nucleophosmin and fibrillarin, and where ribosome assembly occurs. Despite the importance of the rDNA locus, it is largely unknown how chromatin structure at rDNA is regulated. The major goals of the proposed research is to determine how new transposable elements are recognized and how and why chromatin regulates sorting and separation of nascent ribosomes. Guided by the strong preliminary data, we propose to pursue two Specific Aims to understand biology of repetitive elements. We will determine what features in invasion of new transposable elements are recognized by the host and which host machineries can discover those elements (Aim 1). Moreover, we will combine cryo-EM with biochemistry and genetics to determine the role of chromatin in ribosome biogenesis (Aim 2). Together, our proposed studies will have broad impact in chromatin field by showing how chromatin regulates ribosome biogenesis and how insertions of new transposons are recognized by the host. Our long-term goals are to understand the regulation of genome expression by chromatin and discover why mutations in chromatin proteins lead to the formation of cancer cells.
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