Global Regulation of Gene Expression by the NMD Pathway in Yeast

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

The Upf proteins that promote nonsense-mediated mRNA decay (NMD) are best known for their role in RNA surveillance, a mechanism that eliminates aberrant transcripts that arise primarily through errors in gene expression. In this research, the principal investigators plan to investigate the role of the Upf proteins in controlling the levels of expression of a substantial subset of protein-coding genes in S. cerevisiae, but for purposes unrelated to RNA surveillance. Recently, the mRNA targets of NMD were identified by a global estimation of RNA decay rates. About one third of the targeted mRNAs produce proteins known to affect either chromosome or cell surface dynamics. Experiments are planned leading to a possible connection between NMD and the environmental stress response (ESR). In ESR, yeast cells adapt to suboptimal environments through global changes in the gene expression program. Like the transcripts affected by NMD, many of the transcripts affected by the ESR code for proteins that influence chromosome and cell surface dynamics. The levels of the transcripts coding for the Upf proteins do not change as part of the ESR. However, NMD might be connected to the ESR through post-translational protein modifications that respond to changes in environmental conditions. Two proteins required for NMD, Upf1p and Upf2p, are phosphoproteins. The principal investigators plan to test the model that the natural mRNA targets of NMD and the ESR are inter-connected through the phosphorylation of Upf proteins and that Upf phosphoproteins may function as ESR sensors. The big unanswered question about NMD is whether the Upf proteins dynamically regulate gene expression in response to the environment. This project is of general significance to the public because the NMD pathway exists in humans and it has been shown that about one third of all human genetic disorders are caused by mutations that are affected by NMD. In addition, the research contains a plan for integrating research and education by focusing on a group of students who are underserved, under-represented and all but invisible to the academic community - learning disabled (LD) students. Each summer, one LD undergraduate from the UW-Madison campus will be offered a nine week supervised summer research experience in the lab working on experiments in this proposal. The students will be identified through collaboration with the UW McBurney Disability Resource Center. Students will join an existing summer program organized by the UW Center for Biology Education, the "Summer Research Program" (undergraduates from under-represented groups). The summer research experiences will encourage LD students to pursue advanced degrees and professional careers in science. Inclusion of LD students who typically think out of the box and approach problems using alternative learning styles will enhance science and their contributions will benefit society.