PharmSci Research Seminar Series: Kristin Koutmou

CA

Speaker:
Kristin Koutmou, PhD
University of Michigan

Title
Incorporationand molecular level consequences of uridine modifications in mRNAs

Abstract
Cells face the daunting challenge of synthesizing thecorrect number of proteins at the right time with high fidelity. Messenger RNAs(mRNAs) serve as theblueprints for protein synthesis by the ribosome, and thepost-transcriptional modification of mRNA presents one avenue for cells toregulate protein production.The recent discovery ofmRNA chemical modifications has generated tremendous excitement because thesemodifications have the potential to regulate mRNA function and control proteinexpression levels. Pioneering work on mRNA modifications haveimplementedsequencing-based methods to map the location of individual chemicalmodifications acrossall ofthe RNA molecules in a cell. Despite arapidlygrowing recognition of their importance, fundamental questions regarding theidentity, prevalence and functional consequences of mRNAmodifications remainto be answered. We are working tofill these critical knowledge gaps and establish a quantitative andmechanistic basis forunderstanding how mRNA chemical modifications impactprotein synthesis at the molecular level.The work presented heredemonstrates theconsequences of modifying a series of individual uridine nucleobasepositions on the speed and accuracy of the ribosome, and presents evidencesuggesting a new framework for conceptualizing how key uridine modifyingenzymes (pseudouridine synthases) select their mRNA targets.