Clare Boothe Luce Assistant Professor of Chemistry & Biochemistry
University of Notre Dame
RNA structure is largely viewed as being single stranded or double stranded, although triple-stranded RNA structures were deduced to form in test tubes over 60 years ago. Despite this early discovery, only a handful of RNA triple helices have been validated in eukaryotic cellular RNAs. The long-term goal of the Brown laboratory is to understand the cellular, biochemical, and structural roles of RNA triple helices using the MALAT1 triple helix as a model. This triple helix forms at the 3′ end of a cancer-promoting long noncoding RNA, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), and is required for the accumulation of MALAT1 in cells. We recently discovered that the MALAT1 triple helix interacts with METTL16 (methyltransferase-like protein 16), an RNA methyltransferase. The Brown laboratory is exploring several key questions. What is the cellular function of METTL16 and the METTL16-MALAT1 complex? Does METTL16 play a role in cancer? Does the METTL16-MALAT1 complex contribute to the molecular function of MALAT1 in cancer? To investigate these questions, we are using in vitro and cell-based biochemical methods. Ultimately, these mechanistic studies of the MALAT1 triple helix and METTL16 will advance our understanding of their roles in cancer.
- “Structural insights into the RNA methyltransferase domain of METTL16.” A. Ruszkowska, M. Ruszkowski, Z. Dauter, J.A. Brown, Sci Rep. 2018, 8(1), 5311.
- “Methyltransferase-like protein 16 binds the 3′-terminal triple helix of MALAT1 long noncoding RNA.” J.A. Brown, C.G. Kinzig, S.J. DeGregorio, J.A. Steitz, Proc Natl Acad Sci USA. 2016, 113(49), 14013-8.
- “Structural insights into the stabilization of MALAT1 noncoding RNA by a bipartite triple helix.” J.A. Brown, D. Bulkley, J. Wang, M.L. Valenstein, T.A. Yario, T.A. Steitz, J.A. Steitz, Nat Struct Mol Biol. 2014, 21(7), 633-640.
- “Secondary Structural Model of Human MALAT1 Reveals Multiple Structure-Function Relationships.” P.J. McCown, M.C. Wang, L. Jaeger, J.A. Brown, Int J Mol Sci. 2019, 20(22), 5610.