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| Reports on Overseas' Conferences and Meetings |
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Report on the International Workshop on Ataxia-telangiectasia,
ATW2010 |
| Keiji Suzuki, Department of Molecular Medicine |
An international workshop on Ataxia-telangiectasia (AT), ATW2010, was taken place between April 11 and 14, 2010, in Redondo Beach, California. This workshop was held every two years, and every issue from basic to clinical was discussed extensively. This time, Prof. Richard Gatti from UCLA, organized 3-days workshop, whose theme was "from basic research to clinic". More than 200 scientists from all over the world came together, and more than 80 abstracts were submitted, including 34 special talks.
AT is a well known recessive disorder characterized by cerebellar ataxia and telangiectasia. Therefore, the first day was started by discussing the role of ATM mutation on cerebellar ataxia. The major issue of cerebellar dysfunction in AT patients is its cause of abnormality. Serious discussions were made in order to answer to the following question, which is "Whether AT is a developmental disorder or neurodegenerative disorder?" From the studies using AT-mimic mouse, it has been proved that ATM is essential for cerebellum development. However, at the same time, knock-in mouse that enables delayed expression of the mutant ATM gene showed acquired cerebellar atrophy. Therefore, it was concluded that these two mechanisms were involved in cerebellar ataxia.
Defective immune response is other feature of AT. Although V(D)J recombination, which requires non-homologous end-joining, is not totally defective, class switch recombination was dysfunctional in AT. Therefore, acquired immunodeficiency is often diagnosed in AT patients. Class switch recombination is a process, which is initiated by activation-induced cytidine deaminase (AID). The resultant DNA double strand breaks are processed by several factors including XLF, ATMIN, and 53BP1, which are the downstream effectors of ATM. Although the entire process was not fully understood yet, unique chromatin structures, which enable class switch recombination, need these factors to be recruited. Future studies will draw the whole picture soon.
One of the topics of this ATW2010 was a relationship between ATM pathway and oxidative stress response. In vitro experiments demonstrated that ATM kinase activity was activated by H2O2 treatment. The activation was occurred through the formation of ATM dimers, which were mediated by disulfide bonds between two ATM molecules. This is the first evidence showing that ATM molecules can be activated directly by oxidative stress. The experiments also indicated that site-specific cysteine residue was involved in this activation. So far, ATM function has been know to be activated through dissociation of dimer or oligomer to monomer, however, it was demonstrated that ATM dimer, in its specific form, was also able to exhibit activity. There were several questions left before we come to the final conclusion, but, this observation must be the one that take into consideration.
In the second day, we focused on the critical question that is what is the bona fide role of ATM in DNA repair. This question has been answered for many years by several different answers. Defective checkpoint was the first one, by which radiation sensitivity of AT cells was explained. Then, Artemis protein, which has endonuclease/exonuclease activity, has been found to be the target for ATM, and it assumed that DNA repair defect was stem from defective processing of damage ends. Subsequently, another protein named KAP-1 was found to receive ATM-dependent phosphorylation. KAP-1 is a chromatin-associated protein, which is released from heterochromatin upon phosphorylation. It was claimed that dissociation of KAP from heterochromatin facilitated DNA repair in heterochromatin region. This time, another strong candidate was introduced, which was polynucleotide kinase. It is the enzyme called PNKP that has both kinase and phosphatase activity. It can ligate phospho-residues on both sides of the nucleotide ends or remove phospho-moiety from polynucleotide ends. In fact, it has been known for many years as leaning enzyme. A research team lead by Prof Shiloh cataloged PNKP as a substrate for ATM kinase. They confirmed that cells expressing phosphorylation-defective mutants were radiation sensitive. In addition, PNKP is a ubiquitous protein that express through the cell cycle. Therefore, it is quite reasonable to think that PNKP could be the most essential element of ATM-dependent DNA double strand break repair.
Role of ATM function in DNA damage response was thoroughly discussed in that afternoon. Although there was no new factor reported, physiological function of persistent DNA damage was one of the topics to be discussed. As we already reported, ionizing radiation causes large foci that persist for a long time after irradiation. We have claimed that large foci are the essential architecture amplifying DNA damage signal. In the workshop, the similar idea was proposed, although they proposed that it might protect DNA ends, as a molecular shelter. As we know that large persistent foci mark chromatin with mis-rejoind DNA breaks, whereas, unrejoined breaks are also persisted. So, these two ideas are mutually exclusive at this moment, and, our further study should contribute to unify the ideas.
Discussions made in the final day were all about therapy. We all know that it has become a time to think about the patients' treatment. As the AT workshop was launched by Prof. Gatti several years ago, when he met one family with an AT child. He knew what they wanted him to do, and they knew what he could do for them. They established an AT Medical Research Foundation, and at the same time, they started scientific communications by making a platform where every scientist from all over the world comes together and share their information. Today, these efforts are about making the fruits. There are a couple of basic trials going on. For example, AT patients with a specific type of mutation, which causes splicing variants, were able to be treated with antisense morpholino-oligo (AMO). By developing an efficient delivery system through BBB, it significantly improved AT symptom. Within these two years, FDA-approved clinical trials are expected to take place. Treatments of some of the features of AT should be the another way to go. As ataxia is one critical features of AT patients, possible administrations of amantadine and betamethasone were discussed.
Although there were limited numbers of clinicians, one clinical doctor sounded a note of caution that was about lung dysfunction. Since AT patients live with low immunoreactivity, they tend to be suffered by the serious infectious diseases. Sometimes it turns out to be a cause of death. Although much attention has to be paid to the primary defects, the secondary diseases should also be paid much attention.
It was announced that the next meeting will be in November next year. Although it was quite unusual to arrange the meeting so soon, the organizers have decided to do it next year. Many clinicians are expected to come. Together with them, more serious discussions that make the treatment of AT patients possible will be made. Until then, we have to continue our research, which greatly contributes to create the basic idea realizing the more new treatments for the AT patients. |
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