Clare Boothe Luce Assistant Professor of Chemistry & Biochemistry at the University of Notre Dame
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 almost 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.
“Formation of triple-helical structures by the 3′-end sequences of MALAT1 and MENβ noncoding RNAs.” J.A. Brown, M.L. Valenstein, T.A. Yario, K.T. Tycowski, J.A. Steitz, Proc Natl Acad Sci USA. 2012, 109(47), 19202-7.