Now several years later we moved on and we found out that securin bound to this protein which we now called Separase and we didn’t know…and Separase was required for the onset of anaphase. You could not separate sister chromatids without Separase. So we had this model that Separase bound securin. Like in that form it was inactive and the whole purpose of the anaphase promoting complex was to destroy the securin, liberate the Separase and then the Separase went off and did something magical to the chromosomes and maybe the spindle apparatus that would cause the sister chromatids to be pulled to opposite poles. And one of the big questions was what did Separase do, and it was really work that was done by a postdoc in my lab at the time a guy called Frank Uhlmann, who really cracked this problem. We had meanwhile identified many of the proteins that were directly involved in holding sister chromatids together. And again it was the discovery of the anaphase promoting complex and therefore the ability to block cells of metaphase and look for mutants that couldn’t hold sisters together in metaphase that allowed us to identify these proteins which we now call cohesins and the cohesin complex. And we knew that the metaphase-anaphase transition, the cohesin at least one of the subunits of the cohesin sort of disappeared from the chromosomes and we quickly worked out that you needed Separase to do that. And so when Frank arrived in the lab the question is what did Separase do to cohesin such that you wouldn’t destroy cohesion? And we agreed between us that he would take yeast chromatin, and try to purify yeast chromatin with the cohesin on it and then make extracts from cells that had lots of Separase and then see if he could get the Separase to remove the cohesin from the chromosomes. And at this stage I think — I am quite a keen mountaineer and I think I went off to Tibet or somewhere like that to go climbing — and I came back six weeks later or so. And Frank meanwhile had been very busy and he got very excited because he had discovered that these extracts that contain Separase could indeed remove the cohesin from the chromosomes. But the problem was that when it did that the Scc 1 subunit which was what he was assaying, it didn’t just get removed from the chromosomes which is what we thought was going to happen. It actually got proteolytically cleaved. And this is what I mean by, and this was a terribly important discovery. Now at the time — and this is what I was trying to say earlier — that ones’ first reaction was ‘Oh well, it’s a complete artifact. The proteins just, you know yeast extracts are full of proteases, it’s not too surprising to see it cleaved. And so you say ‘Well was it worth going after? Maybe it was just a lot of proteases in the extract.’ And yet if it was real it was terribly important and interesting. And that’s what I mean about this … the discovery’s been made but then your first reaction is ‘Oh well it’s probably all a gigantic artifact.’ And then, and so then there was… we said well if there’s only one way of finding out if it’s an artifact or not, and we actually have to find out where the Scc 1 was being cleaved, we have to map the cleavage sites and once we have done that then we can make mutants which couldn’t be cleaved and then find out if the cleavage was important for anaphase. So Frank, he was a fantastic scientist and he went ahead and did all of that and the rest is history. I mean he discovered that indeed that Separase was a protease, it cleaved Scc1 and the cleavage of Scc1 was absolutely essential for sister chromatid separation, at least in yeast. So that was I think the second very important, very exciting discovery. And you know not only did this shed enormous insight into the chemistry of chromosome segregation and what was going on chromosomes. I mean here the two most of all the excitement about chromosome segregation was all about microtubules and kineticals, and dynamic instability. And one knew almost nothing about the role the chromosomes themselves were playing. And so I think this was a really very exciting…it started off really a major foundation of to study the chemistry of what was going on with chromosomes during mitosis. And it’s something that’s still going on. Because it was fascinating to discover that it was, you had this protein, and all you had to do was to cut it into two and you destroyed the bridge that held sisters. And that is something we’re still trying to work on. How does cohesin actually hold sisters together? How after DNA replication do, the sister DNAs? How do they actually get held together? And why is it that cleavage of the subunit would destroy that connection? So, the discovery that Separase was a protease and what it did was cleave Scc1 was not only terribly interesting, you know, gosh…Proteolytic cleavage is key part of the chemistry of chromosome segregation. But it also ended up shedding a lot of insight into how cohesin might be holding sisters together. Because the way we’re currently thinking about it, we still don’t know for sure if it’s correct, but we think cohesin forms a gigantic ring. And the Scc1 protein is a sort of tripod type ring. And Scc1 is one of the parts of this ring. And when you cleave it you destroy the ring. The ring is opened. And our idea is that DNA somehow trapped inside the ring and therefore what Separase does is it cleaves one part of the ring, it opens the ring and the DNA can then escape. Now we don’t really know if this idea is correct, but the idea very much stemmed from the discovery that the Scc 1 was cleaved, the cleavage, not destruction, was triggering anaphase.

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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