Department of Cellular and Molecular Medicine
Richard A. Padgett, Ph.D.
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (216) 445-2692
Fax: (216) 444-0512
My lab focuses on mechanisms of post-transcriptional RNA processing, particularly pre-mRNA splicing. Over the last few years, both acquired and inherited mutations in various splicing components have been linked to human diseases. We are currently involved in two collaborative projects to define the mechanistic consequences of some of these mutations. The first project focuses on frequent somatic mutations of any of several splicing factors that are found in patients with myelodysplastic syndrome or acute myeloid leukemia. We are examining the biochemical effects of these mutations on the splicing process as well as studying the alterations in gene expression and alternative splicing caused by these mutations. Our goal is to learn how these mutations contribute to cancer and how these effects might be reversed. The second project aims to understand the biochemical and functional effects of inherited mutations in a small RNA (RNU4ATAC) required for the splicing of a subset of genes. These mutations cause a severe developmental disorder characterized by growth retardation, microcephaly and skeletal deformities. Our goal is to identify the target genes whose splicing defects lead to these outcomes. A third, more basic, project in our lab concerns the transcription and splicing of very large mammalian genes. We have recently shown that transcription proceeds rapidly and efficiently through these genes and that splicing of the very long introns found in such genes is also efficient. Current work is focused on defining the genetic signals that promote the correct splicing of giant introns.
In other words ...
Most of our genes have a structure in which sections of sequences that code for proteins (called exons) are separated by sections of non-coding sequences (called introns). When a gene is copied into RNA, machinery in the cell removes the introns and joins the exons together in a process called splicing. Many diseases such as certain types of cancer are either caused by or associated with mistakes in the splicing process or mutations in the splicing machinery. My lab works to understand how these errors lead to disease and how we might correct them.
Singh, J. and Padgett, R.A. (2009) Rates of in situ transcription and splicing in large human genes. Nature Struct. Molec. Biol. 2009; 16: 1128-1133.
He, H. et al. Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science 2011; 332: 238-240.
Padgett, R.A. New connections between splicing and human disease. Trends Genet. 2012; 28: 147-154.
Maciejewski, J.P. and Padgett, R.A. Defects in spliceosomal machinery: A new pathway of leukemogenesis. Brit. J. Haematol. 2012; 158: 165-173.
Kurtovic-Kozaric, A., Przychodzen, B., Singh, J., Konarska, M.M., Clemente, M.J., Otrock, Z.K., Nakashima, M., Hsi, E.D., Yoshida, K., Ogawa, S., Boultwood, J., Makashima, H., Maciejewski, J.P. and Padgett, R.A. PRPF8 defects cause missplicing in myeloid malignancies. Leukemia 2015; 29: 126–136.
Jafarifar, F., Dietrich, R.C., Hizney, J.M. and Padgett, R.A. Biochemical defects in minor spliceosome function in the developmental disorder MOPD I. RNA 2014; 20: 1078-1089.
Polprasert, C., et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 2015; 27: 658-670.