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Work on TF3A with Jonathan Miller


Interest in active chromatin and work on Xenopus
Aaron Klug Scientist
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I decided in 1982 that... by which time we had worked out how DNAs packaged in chromosomes, at least at the first couple of levels. The nucleosome and then the higher order structure, the 300 angstrom fibre and that of course applied to bulk chromatin. But already in the last few years, before that, people had been exploring chromatin by enzymes seeing if there were patches which were... part of them which were accessible to enzyme actions and so on. And the concept grew out of what was called active chromatin. That was chromatin in which the DNA was either being transcribed, turning into RNA or about to be transcribed, poised to transcribe. And the way this was explored was by... as I say, by enzymes, particularly by DNAs one and so on. And there were the beginnings of understanding, a question was that also people found that there were HMG proteins, another class of protein which were found in 300 angstrom fibre a particularly in embryonic forms and so on. But basically I thought that the bulk understanding, at least for the first two levels, and there were higher levels in which the 300 angstrom fibre could be folded but I couldn't see how that was accessible. So I became intrigued by active chromatin and I looked for a system, this was deliberate, I looked for a system, I read the literature, on transcription obviously and also on transcribing chromatin and I looked for a system which we could access biochemically, but to produce material on a large scale for structural studies. And I read about the work of Roeder, that's Bob Roeder who was then at the... St Louis in the USA and Don Brown who was then at the Carnegie Institute of Washington, which happens to be Baltimore, oddly enough, on the system of transcription which is used to make 5S RNA and Xenopus. Xenopus the frog, as a biologist insist on calling it a toad and I'll call it a frog. It's a South African toad. It is a very important animal in biological studies, there's a whole groups work on Xenopus, it's one of the classic animal models. The 5S RNA genes are switched on by a transcription factor called TF3A, TF3A is transcription factor A of polymerase three, there are three different polymerases in your carriers. Bacteria only have one, but there are three different ones all closely related but they are used for different classes. Class two is what makes ordinary; switches on ordinary genes which make... are messenger RNA... polymerase three is what makes RNA which is the final product, such as RNAs going into the ribosomes and so on, and the... so although it wasn't in the main class of... but this is one which is accessible because they showed that there were large quantities of TF3A in immature Xenopus oocytes. And it happened that in our lab was Hugh Pelham newly arrived, he is now the deputy director and he'd worked with Don Brown and he's shown that TF3A was the same as a storage protein, identified by some French work as 40 kilodaltons in size which was thought to be a storage protein for 5S RNA, so this was a real conundrum. The TF3A was both a transcription factor but it also bound to the product of transcription 5S RNA itself. So it bound both the 5Ss RNA gene and the 5S RNA product. Well, we found out it's only in 2003, two years ago, we found how it bound to RNA, actually that's yet another story, it's a quite important postscript to it all, but I'll come to that. But this intrigued me, but the thing that intrigued me most, or rather that attracted me most, was there seemed to be large quantities and... we had Xenopus in the lab because John Gurdon was in the lab so these were taken from oocytes and the way that you do this is that you can extract the material... you stimulate, you put in factors which will promote ovulation in the female frogs and then what the experts do would be to actually cut him open and take out the oocytes, extract them and you can sew them up again, apparently that's what Gurdon did, but cruder people simply kill the frogs and take out the oocytes, so you can get large quantities.

Born in Lithuania, Aaron Klug (1926-2018) was a British chemist and biophysicist. He was awarded the Nobel Prize in Chemistry in 1982 for developments in electron microscopy and his work on complexes of nucleic acids and proteins. He studied crystallography at the University of Cape Town before moving to England, completing his doctorate in 1953 at Trinity College, Cambridge. In 1981, he was awarded the Louisa Gross Horwitz Prize from Columbia University. His long and influential career led to a knighthood in 1988. He was also elected President of the Royal Society, and served there from 1995-2000.

Listeners: Ken Holmes John Finch

Kenneth Holmes was born in London in 1934 and attended schools in Chiswick. He obtained his BA at St Johns College, Cambridge. He obtained his PhD at Birkbeck College, London working on the structure of tobacco mosaic virus with Rosalind Franklin and Aaron Klug. After a post-doc at Childrens' Hospital, Boston, where he started to work on muscle structure, he joined to the newly opened Laboratory of Molecular Biology in Cambridge where he stayed for six years. He worked with Aaron Klug on virus structure and with Hugh Huxley on muscle. He then moved to Heidelberg to open the Department of Biophysics at the Max Planck Institute for Medical Research where he remained as director until his retirement. During this time he completed the structure of tobacco mosaic virus and solved the structures of a number of protein molecules including the structure of the muscle protein actin and the actin filament. Recently he has worked on the molecular mechanism of muscle contraction. He also initiated the use of synchrotron radiation as a source for X-ray diffraction and founded the EMBL outstation at DESY Hamburg. He was elected to the Royal Society in 1981 and is a member of a number of scientific academies.

John Finch is a retired member of staff of the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK. He began research as a PhD student of Rosalind Franklin's at Birkbeck College, London in 1955 studying the structure of small viruses by x-ray diffraction. He came to Cambridge as part of Aaron Klug's team in 1962 and has continued with the structural study of viruses and other nucleoproteins such as chromatin, using both x-rays and electron microscopy.

Tags: Bob Roeder, Don Brown, Hugh Pelham, John Gurdon

Duration: 5 minutes, 45 seconds

Date story recorded: July 2005

Date story went live: 24 January 2008