Universität zu Köln 

Dr. Frank Sprenger

Institut für Biochemie, Genetik und Mikrobiologie, Universität Regensburg
(formerly: Institut für Genetik, Universität zu Köln)
email: frank.sprenger@biologie.uni-regensburg.de
phone: +49-(0)941 943-3167
website

Running time: 2003 – 2007

Abstract

Posttranslational control is a prominent way of regulating cell cycle progression. In this project, we focus on the regulation of Cyclin A turnover by posttranslational mechanisms. First, we will analyse cyclin degradation, which is necessary for exit from mitosis and the establishment of the G1 state. The events leading to cyclin destruction are best understood for B-type cyclins. In contrast, we do not understand how turnover of the important cell cycle regulator Cyclin A is achieved. There are a number of differences between Cyclin B and Cyclin A degradation. Cyclin A proteolysis is initiated before Cyclin B degradation and is not inhibited by the spindle checkpoint. Cyclin A, like Cyclin B, contains a D-box but in contrast to Cyclin B, mitotic destruction does not require this canonical destruction signal. We will delineate the missing destruction element and will analyse how Cyclin A is recognised for destruction during mitosis. The mitotic degradation of Cyclin A is also modulated by DNA-damage. When DNA-damage occurs during S-phase, cells are blocked at the G2-M transition but eventually overcome this block and enter mitosis. In this situation the Cyclin A stability is increased and exit from mitosis is delayed.

We will investigate if phosphorylation on Cyclin A by checkpoint kinases is responsible for this regulation. A modification of Cyclin A by phosphorylation is also a likely mechanism how Cyclin A turnover is regulated outside mitosis, during interphase of the early nuclear cycles in Drosophila embryo. In these cycles mutations in the Chk1 kinase increase Cyclin A stability and this interferes with normal cell cycle progression. Finally a characteristic cleavage in the N-terminal part of Cyclin A has been observed in vertebrates and under in vitro conditions using Drosophila extracts. We will determine if Cyclin A cleavage is biological relevant and determine the regulation of this process. Overall, these studies should provide essential insights into the regulation of the cell cycle regulator Cyclin A by posttranslational mechanisms during normal cell cycle control and its response to stressed conditions, like DNA-damage.

Publications resulting from the project:

Ramachandran, V., Matzkies, M., Dienemann, A., and Sprenger, F. (2007). Cyclin A degradation employs preferentially used lysines and a cyclin box function other than Cdk1 binding. Cell Cycle. 6, 171-81.

Dienemann, A., and Sprenger, F. (2004). Requirements of Cyclin A for mitosis are independent of its subcellular localisation. Curr. Biol. 14, 1117-1123.?