The Kielkopf lab investigates the molecular structures and interactions among key pre-mRNA splicing factors in human genetic diseases and hematologic malignancies (Trends Genetics 2017). Our recent structures of U2AF2 bound to a range of splice site signals provide a basis for understanding disease-causing mutations in the splice sites of gene transcripts (PNAS 2014; Nature Commun. 2016). As a step towards viewing the architecture of multi-subunit pre-mRNA splicing factor complexes, we revealed phosphorylation-induced conformational changes in the splicing factor subunit SF1 bound to U2AF2, and demonstrated that the phosphorylated interface is essential in vivo (Structure 2013). We have further shown that recurrent, cancer-associated mutations of U2AF1 alter its RNA interactions (Leukemia 2014; PLOS Genetics 2017). Now, our immediate goal is to determine roadmaps of the key interactions among higher order 3' splice site complexes, and in future phases of the project, assist the development of therapeutics targeted at the level of pre-mRNA splicing.
We are grateful to the following organizations for research funding:
National Institutes of Health:
R01 GM070503: Molecular Recognition During pre-mRNA Splicing
R01 GM117005: Structural Control of Human Co-factors for Retroviral Gene Expression
Edward P. Evans Foundation:
Research Discovery Grant: Structural mechanisms & targeting of MDS-relevant pre-mRNA splicing factors