Page 11 - Rappaport Institute Magazine 2024

BIOCHEMISTRY
The ubiquitin system for protein degradation and its roles in the control of cell division
The selective degradation of cellular proteins carries out processes essential for living organisms. Previous work from my laboratory has shown that proteins are targeted for degradation by linkage to a small protein, ubiquitin. More recently, I became interested in the roles of the ubiquitin system in the control of cell division, since cancer is due to loss of cell division control. A centrally important ubiquitin ligating enzyme in this process is the Anaphase-Promoting Complex/Cylosome (APC/C), which targets for degradation regulators of cell division. The activity of APC/C is controlled by the mitotic checkpoint system, a surveillance mechanism that ensures accurate segregation of chromosomes in mitosis. The mitotic checkpoint inhibits the APC/C by the assembly of a Mitotic Checkpoint Complex (MCC) (Figure). I am using biochemical approaches to elucidate the molecular mechanisms of the regulation of APC/C in mitosis. Since cancer cells are characterized by dysregulation of cell division and loss of accuracy of chromosome segregation, insights gained from this research may have important implications in new approaches to the cancer problem.
Selected Publications
ˆ Sudakin, V., Ganoth, D., Dahan, A., Heller, H., Hershko, J., Luca, F.C., Ruderman, J.V. and Hershko, A. (1995). The cyclosome, a large complex containing cyclin-selective ubiquitin ligase activity, targets cyclins for destruction at the end of mitosis. Mol. Biol. Cell 6, 185-198.
ˆ Sitry-Shevah D, Kaisari S, Teichner A, Miniowitz-Shemtov S. and Hershko A. (2018) Role of ubiquitylation of components of mitotic checkpoint complex in their dissociation from anaphase-promoting complex/cyclosome. Proc. Natl. Acad. Sci. USA, 115, 1777-1782.
ˆ Sitry-Shevah, D., Miniowitz-Shemtov. S., Teichner, A., Kaisari, S. and Hershko, A. (2022) Role of phosphorylation of Cdc20 in the regulation of the action of APC/C in mitosis. Proc. Natl. Acad. Sci. USA, 119 (35) e2210367119
Grants and Awards
1999 – The Emet Prize for Medicine, Israel (with A. Ciechanover) 2000 – Member, Israel Academy of Sciences
2000 – Albert Lasker Basic Medical Research Award (with A. Ciechanover and A. Varshavsky)
2002 – The E. B. Wilson Medal of The American Society of Cell Biology (with A. Varshavsky)
2003 – Foreign Associate, National Academy of Sciences, USA
2003 – Foreign Member, American Philosophical Society
2004 Nobel Prize in Chemistry (with A. Ciechanover and I. A. Rose)
hershko@technion.ac.il
Avram Hersko Lab
Avram Hershko, MD, PhD Distinguished Technion Professor of Biochemistry
MD, 1965 – The Hebrew University of Jerusalem, Israel
PhD, 1969 – The Hebrew University of Jerusalem, Israel
08-09
08-09
The mitotic checkpoint system is activated by the lack of attachment of duplicated chromosomes to the mitotic spindle. This promotes the assembly
of MCC, a strong inhibitor of APC/C. After all chromosomes are correctly attached to the mitotic spindle MCC is disassembled, APC/C becomes active and targets for degradation securin, an inhibitor of anaphase initiation. I am investigating the mechanisms of the mode of inhibition of APC/C by MCC and a variety of processes by which MCC is disassembled, thus allowing cells to exit mitosis. Ub, ubiquitin.