马克·施密特博士

研究抽象

The main goal of our research is to determine the function and regulation of the ribonucleoprotein endoribonuclease, 核糖核酸酶MRP, in the cell division cycle in late telophase. The incorrect regulation of cell division is the basis of all cancers. Understanding the details of how cell division is regulated and controlled is essential for controlling cancer and finding cures. Previous work had found that 核糖核酸酶MRP is directly involved in the late stages of the cell division cycle by regulating the activity of the cyclin dependent kinase. Cells that are defective in 核糖核酸酶MRP have a delayed telophase. We have made extensive progress in identifying the exact molecular mechanism of this regulation. We have found that at a particular time in the cell division cycle the 核糖核酸酶MRP enzyme is released from the nucleus a compartment in the cell where it is kept sequestered. The release of this endoribonuclease allows it to breakdown specific m核糖核酸s for B-type cyclins that are required for the activity of the cyclin dependent kinase, the promotes inactivation of the cyclin dependent kinase and the termination of the cell cycle. These studies have also led us to discovering a new organelle, the TAM (Temporal Asymmetric MRP) body. We have found that this structure is P (processing) body “喜欢”. But in contrast to P bodies that are found throughout cells and the cell cycle, TAM bodies are temporally and spatially assembled organelles whose function is to degrade specific m核糖核酸s at a discrete time and location in the cell cycle. 核糖核酸酶MRP localizes to this organelle during mitosis and it is in this location that the B-cyclin m核糖核酸s are degraded.

核糖核酸酶MRP is conserved throughout eukaryotes and mutations in the human 核糖核酸 component have implicated this enzyme as an essential growth regulator. Human mutations cause Cartilage Hair Hypoplasia (CHH) a recessively inherited disorder characterized by short stature, 脆弱的头发, 贫血, 免疫缺陷, and a predisposition to the development of lymphomas and other cancers. Data from our lab in collaboration with others has shown that human 核糖核酸酶MRP is also playing a role in destabilizing certain m核糖核酸s. Failure to normally degrade certain m核糖核酸s could easily cause the cell cycle delay seen in the human disease and the resulting phenotypes. Hence, these studies will have direct implications on human disease and pathogenesis.

Selected Publications:

Esakova O, Perederina A, Quan C, Schmitt ME, Krasilnikov AS. Footprinting analysis demonstrates extensive similarity between eukaryotic RNase P and 核糖核酸酶MRP holoenzymes. 核糖核酸. 2008 Aug;14(8):1558-67. 2008年6月25日.

Perederina A, Esakova O, Koc H, Schmitt ME, Krasilnikov AS. Specific binding of a Pop6/Pop7 heterodimer to the P3 stem of the yeast 核糖核酸酶MRP and RNase P 核糖核酸s. 核糖核酸. 2007 Oct;13(10):1648-55. Epub 2007 8月23日.