A-T Society: Research Strategy
The Society supports research projects that increase understanding of A-T but with the emphasis, where possible, on bringing timely benefits to families. The types of award available are normally postgraduate studentships, equipment grants, A-T conferences and travel awards.
The majority of our research funds are directed to specific projects at The Cancer Research UK Institute for Cancer Studies, University of Birmingham, under the direction of Professor A M R Taylor who is the UK’s leading researcher into A-T. Currently the Society is funding one research project at the Institute. This is to support a clinical research fellow investigating links between A-T mutations and the severity of the disease. However if funds are available we do support other A-T research projects in keeping with our strategy.
Medical
Advisers to Society
1. Dr Graham Davies
Consultant Paediatrician/Immunologist
Great Ormond Street Hospital
London
2. Dr Nicholas P Davies
Consultant Neurologist
The Queen Elizabeth Hospital
Birmingham
3. Professor Christine Harrison
Cytogenetic Group
University of Southampton
4. Dr Louise Izatt
Consultant Clinical Geneticist
Guy’s & St Thomas’ Hospital
London
5. Prof S Jackson
The Gurdon Institute
University of Cambridge
6. Dr Carmel McConville
CRUK Institute for Cancer Studies
University of Birmingham
7. Professor J Varley
Paterson Institute for Cancer Research
Manchester
8. Dr Leanne Wiedemann
Stowers Institute for Medical Research
Kansas City
U.S.A
9. Professor Nicholas Wood
Consultant Neurologist
National Hospital for Neurology and Neurosurgery
London
10.
Professor B D Young
ICRF Department of Medical Oncology
St Barts.’ Hospital Medical College
London
International A-T Workshop 2008
A team of scientists, researchers and clinicians from the UK, some of them sponsored by the A-T Society, travelled to Japan in April to take part in an international workshop on A-T. Maureen Poupard was also there, representing the Society.
Maureen writes:
The
International A-T Workshop took place from 22 - 26 April in Kyoto, Japan.
These scientific meetings are held approximately every two years and bring
together many researchers who are involved with A-T research to share information,
forge collaboration and drive the research effort forward.
Talks began at 8am and finished at 10 pm. A typical day contained 23 speakers – making it all rather intense! As well as all the talks, further information about A-T research work that had been carried out was also disseminated via a poster presentation. 127 posters were exhibited during the course of the workshop, and were left on display at the back of the hall for people to peruse. A couple of hours was also laid aside for their authors to be in attendance so that they could be quizzed about their work.
Over 260 people attended from Japan, the USA, Italy, Israel, Canada, Australia, Singapore, the UK, Poland, Germany, Spain, Switzerland, Korea, Netherlands, Denmark, Sweden, France, Norway and Hong Kong.
Please
download the Summer
Newsletter to read further reports from the Japan workshop.
Ataxia-Telangiectasia - Research Update
There have been a number of important recent publications on Ataxia--Telangiectasia or rather the ATM protein. I will only mention two of these. As you are all aware, the ATM protein normally functions as part of a battery of proteins that form the cells' response to damage to the genetic material, DNA. Following damage, the cell should not replicate itself until the damage is repaired. If the damage is too great, perhaps the best option is to remove the cell altogether.
The nature of the cellular response is very complex and must follow an initial recognition of the damage. The mechanisms by which damage is first recognised are not well understood and this is particularly true of the type of damage to which ATM responds, the DNA double strand break. What is known, however, is that ATM is an important player in different responses that the cell makes early after damage is induced. So, one type of activity that ATM possesses is to be able to quickly modify other proteins; it is a kinase. It can modify a range of different proteins that will result, for example, in the cell not replicating itself following any damage and if the damage is too great, modification of other proteins can result in the destruction of that particular cell. These effects are reasonably well understood.
If we go back, however, to the moment between these two, after the recognition but before the response, ATM must itself be ‘made aware’ of the damage before it can respond. The ATM protein must be in a state of ‘inactive preparedness’. In a very important paper published in Nature in January, Christopher Bakkenist and Mike Kastan showed that the ATM protein normally exists in the cell as a couplet, two molecules of ATM clasped together head to toe, in an inactive form. In order for the protein to be able to modify other proteins in response to damage it must first be released from the couplet. The secret of this, discovered by Bakkenist and Kastan is that the ATM protein can modify itself. What occurs, therefore, is a reciprocal modification of the two parts of the couplet. After damage is caused to the cell this results in the ATM modifying itself which allows the disruption of the couplet and so the ATM is ‘unlocked’ and can go on to modify other proteins in a cascade of events. They also showed that ATM was very sensitive at detecting damage and even at low levels of damage over half of all the cellular ATM was activated and ready to modify other proteins. The authors believed that the breaks in the DNA have the capacity to signal to ATM at quite a distance in the cell and they make the suggestion that DNA breaks induce changes at the level of the chromosome and it is this that leads to the activation of ATM. Interestingly, this suggests that a lot of activated ATM is not at the site of the damage.
There are many questions that arise from this work. For example: what happens when a normal molecule of ATM and a mutant molecule form the couplet? The answer is that one partner may be able to modify the other but the mutant protein may not be able to reciprocate and so there is no release and no activation. What happens in the case of two mutant proteins, with some residual capacity to modify themselves, present in a couplet? Presumably, there will be a degree of release followed by some modification of other proteins. This important work has revealed a crucial secret of ATM and we can be sure that this work will develop further.
On the question of the role of the chromosome in responding to DNA damage, you will be interested to know that Grant Stewart, formerly a PhD student supported by the A-T Society, published a paper in Nature in February describing a new protein called MDC1. This protein forms a complex with part of the chromosome structure and helps to bring other proteins to the site of the damage. It was possible in cells in culture to remove functional MDC1 protein from the cell, and one result that this gave was an increase in sensitivity of the cells to ionising radiation, just like A-T cells. Again, this finding reiterates the complexity of the cellular response to damage to the DNA.
On an even more esoteric note, a recent letter to the Editor of the Journal ‘Cell’ by Perry and Kleckner, described the ATM protein as one of a group of ‘Giant HEAT repeat Proteins’. HEAT, here is an abbreviation for a technical term that I won’t go into. The only point I wanted to make was that here is a group of structural protein chemists who have been able to classify ATM as one of a group of very large proteins with particular characteristics that they have recognised in other large proteins. The part of ATM that they were concerned with is different to the part that I have described as modifying other proteins. Possibly such work will help an understanding of other functions of ATM.
Finally, returning to Ataxia-Telangiectasia, a paper by Farr et al, in the American Journal of Ophthalmology, last December, described in some detail the problems that A-T patients have with their eyes. This work was the result of an analysis of 63 A-T patients, between the ages of 2 and 28 years seen at the A-T clinic at Johns Hopkins Hospital, Baltimore. The proportions of patients with different abnormalities of eye movement are given. An important conclusion of the authors was that poor muscular control and abnormal eye movements may lead to the reading difficulty reported by A–T patients. This is a nice example of the results of observations on A-T patients in a clinic.
As I have said before these are comments on just a few of the papers published recently but I think it they provide a ’feel’ for the range of the research interest in A-T and ATM. I am sure that the coming months will bring many more publications on A-T and ATM and with it an increased understanding of the workings of this protein.
A.M.R.Taylor,
CR UK Institute for Cancer Studies,
The University of Birmingham,
Vincent Drive,
Edgbaston,
Birmingham,
B15 2TT
Tel:
+44 (0)121-414-4488
FAX; +44 (0)121-414-4486
Email : A.M.R.Taylor@bham.ac.uk
References
Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature (2003) 421: 499-506.
Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ. MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature (2003) 421:961-966.
Perry
J, Kleckner N.The ATRs, ATMs, and TORs are giant HEAT repeat proteins.
Cell (2003) 112:151-155.
Farr AK, Shalev B, Crawford TO, Lederman HM, Winkelstein JA, Repka MX. Ocular manifestations of ataxia-telangiectasia. Am J Ophthalmol. (2002)134: 891-896.
Prof
A.M.R.Taylor
Research
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