Avram Hershko, MD, PhD
Distinguished Technion Professor of Biochemistry
MD, 1965 - The Hebrew University, Jerusalem
PhD, 1969 - The Hebrew University, Jerusalem
The ubiquitin system for protein degradation and its roles in the control of cell division.
Protein degradation is a fundamental cellular process, yet little attention has been paid to the biochemical mechanisms involved in its precise regulation and high degree of selectivity. Previous work in my laboratory has shown that specific proteins are targeted for degradation by covalent linkage to a small protein, ubiquitin. Our research group has also elucidated many of the basic biochemical steps in the ubiquitin-mediated protein degradation pathway (Figure; upper panel). More recently, I became interested in the roles of ubiquitin-mediated protein degradation in the control of the cell division cycle. Cell division is driven by oscillations in the levels of regulatory proteins such as cyclins, inhibitors of cyclin-dependent protein kinases and inhibitors of anaphase initiation. The programmed degradation of cell cycle regulatory proteins is essential for progression to the next stage of the cell division cycle. My laboratory has described several ubiquitin ligase systems that are involved in the degradation of major cell cycle regulators. Of those, I am focusing now on the regulation of the Anaphase-Promoting Complex/Cyclosome (APC/C), a multisubunit ubiquitin ligase essential for exit from mitosis. The activity of APC/C is intricately regulated in the cell cycle and it is the target of the mitotic checkpoint system, a surveillance mechanism that ensures the accuracy of chromosome segregation in mitosis. The mitotic checkpoint system is turned on as long as not all chromosomes are correctly attached to the mitotic spindle and delays the initiation of anaphase by promoting the assembly of inhibitors of APC/C, such as the Mitotic Checkpoint Complex (MCC). Only after all chromosomes are correctly attached to the mitotic spindle the checkpoint system is turned off, MCC is disassembled, APC/C becomes active and allows chromosome separation by promoting the degradation of the anaphase-inhibitory protein securin (Figure; lower panel). The biochemical mechanisms involved in the assembly and disassembly of MCC, and the mode by which MCC and other checkpoint inhibitors regulate the activity of the ubiquitin ligase APC/C, remain obscure and are the subject of our current investigation. Since accurate chromosome segregation is essential to prevent aneuploidy, and since aneuploidy and chromosome instability are prevalent in most cancers, these studies are of obvious biomedical significance.
(Upper panel) Basic biochemistry of the ubiquitin system for protein degradation. (a) Original hypothesis proposed in 1980. (b) Current information concerning the main enzymatic reactions of the ubiquitin proteolytic pathway. Ubiquitin (Ub) is ligated to the protein substrate by the consecutive action of three types of enzymes, E1-E3. The action of E3 ubiquitin ligases determines much of the selectivity and the regulation of protein degradation. Proteins ligated to polyubiquitin chains are degraded by
the 26S proteasome. E1, ubiquitin-activating enzyme; E2, ubiquitincarrier protein; E3, ubiquitin-protein ligase; DUB, deubiquitylating
enzyme; UCH, ubiquitin C-terminal hydrolase. (Lower panel) Role of APC/C ubiquitin ligase in mitotic checkpoint.
Miniowitz-Shemtov S, Eytan E, Ganoth D, Sitry-Shevah D, Dumin E, Hershko A. 2012. Role of phosphorylation of Cdc20 in p31comet-stimulated disassembly of the mitotic checkpoint complex. Proc. Natl. Acad. Sci. USA 109, 8056-8050.
Teichner A, Eytan E, Sitry-Shevah D, Miniowitz-Shemtov S, Dumin E, Gromis J, Hershko A. 2011. p31comet promotes disassembly of the mitotic checkpoint complex in an ATP-dependent process. Proc. Natl. Acad. Sci. USA 108, 3187-3192.
Miniowitz-Shemtov S, Teichner A, Sitry-Shevah D, Hershko A. 2010. ATP is required for the release of the anaphase-promoting complex/cyclosome from inhibition by the mitotic checkpoint. Proc. Natl. Acad. Sci. USA 107, 5351-5356.