It is now clear that regulatory non-coding RNAs (ncRNAs) play important roles in the development of human cancer. While it is known that cancer-related ncRNAs vary greatly in their size and sequence, the role of their natural chemical modification in both normal and transformed cells is poorly understood. Recent studies have revealed that the small molecules CoA and NAD cap the 5'end of small RNAs in divergent bacteria. The function of these novel RNA modifications is completely unknown. I propose that small RNAs, including microRNAs and siRNAs in eukaryotes and CRISPRs in prokaryotes possess these 5'modifications. In addition, I believe that these modifications confer on RNAs an ability to covalently interact with the proteome. I will use biochemistry and genetics techniques to determine whether or not coenzyme-small RNA conjugates are present in the nematode C. elegans, how those RNAs become linked to the proteins and what novel properties such RNA-tagged proteins would show. Because cancer cells are known to have both altered metabolic states as well as aberrant expression of ncRNAs, it is possible that coenzyme-capped RNAs play a pivotal role in oncogenesis and may represent a previously undetected meeting point between small RNA biology and cellular metabolism.
The purpose of this project is to contribute to the public's understanding of the mechanisms that cause human cancer. Many cancer-related genes are present in laboratory model organisms such as the round worm Caenorhabditis elegans. Understanding how these genes function and interact is instrumental in progressing towards our fight against cancer.
|Newman, Martin A; Ji, Fei; Fischer, Sylvia E J et al. (2018) The surveillance of pre-mRNA splicing is an early step in C. elegans RNAi of endogenous genes. Genes Dev 32:670-681|