EXPLORATION OF RNA METABOLISM FOR DRUG DISCOVERY

Diaz-Saez L, Mathea S, Salah E, Bock M, von Delft F, Knapp S, Arrowsmith CH, Edwards AM, Bountr C and Huber K.

Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford, Oxford, United Kingdom

Abstract

mRNA metabolism involves modulation of the mRNA stability, splicing, synthesis of microRNAs and mutagenesis. Alterations of these processes lead to differential protein expression and/or function, and can cause disease. More specifically, abnormal mRNA processing has been correlated with cancer development and other diseases such as Aicardi-Goutieres syndrome and amyotrophic lateral sclerosis. One of the mRNA destabilising mechanisms is mediated by the removal of the 5’-end cap. This can be catalysed by the mRNA decapping complex, mainly formed by DCP2 (a Nudix protein responsible for the decapping activity), DCP1A/B, DDX6, EDC4 and EDC3. Additionally, mRNA stability can be modulated through the cleavage of the polyadenylation signal (PAS) by the Cleavage Factor Im (CFIm) complex, comprising three proteins: CFIm25 (Nudix protein catalysing the cleavage), CFIm59 and CFIm68. To further study the roles of the Nudix proteins DCP2 and CFIm25 in the cell, we aim to functionally and structurally characterise these proteins towards the development of chemical probes. We present the preliminary data on the exploration of DCP2 and CFIm25 for drug discovery.

Keywords: mRNA metabolism, drug discovery.