Recorded: 20 May 2004
I think one of my, I think, there were probably two in the last ten years. One was when we isolated— and I have to say none of these things— I think probably the best work that my lab has done— has been done after I stopped doing experiments myself so none of these things were done by me. They were always done by students, or postdocs, or technicians. But even though I wasn’t working with my own hands I’ve always worked quite closely at least intellectually with people in my lab so I’ve always felt very involved. And I think the— probably the first case was when we were isolating mutants that would be defective in cyclin degradation. So you know, CDC2 moved on and cyclins came in and one realized that— from the work of Paul [Nurse] and from Tim Hunt, and a lot of other people— that CDC2 was cyclin B activation drove cells into mitosis. And Tim discovered cyclins as being proteins that aren’t fluctuated during the cell cycle. And it soon became apparent that their degradation played a very important role in getting out of mitosis. And so the big question was, and so what would happen is cyclins would accumulate and you go into mitosis. And then suddenly at around the time that the mitosis took the sister chromatids separated, the cyclin suddenly became unstable. And it was a very interesting question for everybody. ‘What caused cyclin from being a very stable protein to being a very unstable protein? And the biochemists were active and soon discovered that it probably involved ubiquitination of cyclins. And for a while people thought erroneously, and our lab was largely responsible in showing that it was erroneous. That the actual destruction of cyclins per se was what triggered this most dramatic event of all of in mitosis, which was the separation of sister chromatids of the metaphase-anaphase transition. We showed very clearly that wasn’t the case at least in yeast and I think that’s been largely borne out in other organisms subsequently. But nevertheless, one wanted to know why cyclins suddenly became unstable at that stage. And so we set out to identify the genes that might be involved in causing cyclins to become unstable. We were able to develop an assay for that, and I won’t go into the details but when we eventually identified some of the genes we realized that these genes were required for cyclin proteolysis.
And we now know that the genes we’d identified were all part of this huge ubiquitin protein ligase that causes cyclins to be ubiquitinated which then targets them off to the proteasome and that’s how they actually get degraded. But when we got these mutants, yes they were defecting the cyclin degradation, but at the same time these mutants couldn’t initiate anaphase. The cells would get stuck in metaphase and with high cyclins, but they also couldn’t initiate anaphase. And we knew the failure to initiate anaphase was not due to a failure to destroy cyclins. So you know then the penny really dropped - that the cyclin degradation machinery was required to destroy something that was required to initiate anaphase. So that was I think a very important step that really finally really proved that point. And that really effected research in my lab and a lot of other labs I think as well to try and then hunt down, what was it you had to destroy to initiate anaphase.
And that led very quickly to the discovery of a protein called securin by Doug Koshland’s lab and Mitsuhiro Yanagida’s lab. And it very soon became clear that the thing that the anaphase, this ubiquitin protein ligase was destroying cyclins. It also destroyed securin it was the destruction of securing that triggered anaphase. So that was one discovery that really changed what my lab did and I think changed what a lot of labs did, and it really got us into the biochemistry or rather the chemistry of chromosome segregation. And that is, it’s about ten years later and we are still very, a lot of us are still studying that.
Kim Nasmyth is the Head of the Biochemistry Department of the University of Oxford and the Whitley Professor of Biochemistry. He was educated in Great Britain and earned his Ph.D in Zoology from the University of Edinburgh. He did his postdoctoral studies in Ben Hall's labolatory in Seattle Washington. He spent one year at Cold spring Harbor Laboratories as a Robertson Fellow. He was the Director of the Research Institute of Molecular Pathology (IMP) in Vienna (Austria). He is one of the discoverer of cohesin, protein complex which during cell division is crucial for faithful chromosome segregation.
Professor Nasmyth is a fellow of the Royal Society and Foreign Honorary Member of the American Academy of Arts and Sciences. He has received many scientific honours, including the Max Perutz Prize, the Louis Jeantet Prize for Medicine and the Wittgenstein Prize and the Unilever Science Prize.
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