Roles of RNA methylation writers in gene expression and cancer

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2020-12

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Abstract

After a relatively slow start, the field of RNA epigenetics has exploded in recent years. As with DNA, RNA modifications are controlled by proteins capable of post-transcriptionally writing, reading, or erasing position-specific modifications to affect downstream processes. In this dissertation, we focus on the molecular mechanisms surrounding RNA modification writers and how they contribute to human cancer. Our studies center upon BCDIN3D, a Bin3 domain-containing RNA methyltransferase. A 2012 study (Xhemalçe et al.) established BCDIN3D catalytic activity on the 5’ mono-phosphate of specific precursor miRNAs while intriguingly showing that downregulation of BCDIN3D in human triple negative breast cancer cell line MDA-MB-231 led to decreased transformation and invasion in vitro. In order to understand the mechanisms underlying these effects on human cancer cells, we performed in depth analyses of the RNA and protein interactome of BCDIN3D. Sequencing of BCDIN3D-associated RNAs through TGIRT-seq revealed a dominant tRNA [superscript His] interaction and a new role for BCDIN3D in regulation of miR-4454, which is possibly derived from noncanonical processing of the tRNA [superscript His] 3’ end. Proteomic analysis of BCDIN3D interactors unexpectedly revealed the presence of two 5-methylcytosine (m⁵C) RNA methyltransferases, NSUN2 and NSUN5. While the interaction with NSUN2 is likely related to tRNA [superscript His] m⁵C modification, characterization of NSUN5 unearthed a number of intriguing new putative targets and pathways influenced by m⁵C activity, as well as promise for future therapeutic development in human cancers.

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