PI3K-Like Protein Kinases
DNA damage response is related to cellular homeostasis
Prof Yossi Shiloh - Tel Aviv University, Tel Aviv, Israel
Our DNA is attacked all the time by various DNA damaging agents, most of which come from within the cell. It’s an enemy from within and it’s quite incredible the number of hits and insults that the DNA has to suffer during one day. This is without mentioning outside radiations and chemical carcinogens in the environment. So very sophisticated mechanisms had to evolve in order to protect the DNA and maintain the stability and the integrity of our genome in the face of this constant attack. So the DNA damage response is a very complex and elaborate network of responses which includes, of course, DNA repair mechanisms but also many signalling branches that control and actually modulate various metabolic circuits while the DNA is being repaired. So altogether the DNA damage response is one of the most elaborate and complex cellular responses to any stimulus.
Can you elaborate on the various diseases and syndromes related to problems in DNA damage?
Maintaining the stability and the integrity of the DNA is critical for cellular homeostasis and for maintaining the normal lifecycle of the cell and for preventing undue cell death or, even worse, carcinogenesis. Any defect, any inherited defect, in any of these mechanisms can result in a whole variety of symptoms, syndromes, diseases. Actually it’s quite a broad variety, the most acute diseases, the most severe diseases that are caused by genetic defects in the DNA damage response are very, very severe inherited diseases that include tissue degeneration, cancer predisposition, various malformations so cancer, this predisposition and sometimes premature aging are very typical for these diseases.
These are very severe diseases, fortunately they are rare but, in addition, there’s a whole variety of conditions, some of which are quite subtle and some of them may appear later in life and may be regarded as chronic diseases that are totally unrelated to maintenance of genome stability. But, in fact, the genetic components in these conditions or diseases is tightly or closely related to maintenance of genome stability. Because of the fact that there are so many proteins that are involved in maintenance of genome stability and behind each protein there is a gene and a gene can be mutated in many ways, obviously in people there are numerous combinations that reduce to various extents the efficiency at which they maintain the stability of their genome. So, like I said, the most extreme, acute cases are those terrible diseases but then there’s a whole variety, a whole continuum of conditions that are actually caused in a large part by more moderate or even subtle defects in maintenance of genome stability. These result in, for example, various forms of immune deficiency, neurodegeneration, cancer predisposition and, in general, a very strong genetic component that determines the pace at which we age is related, intimately related, to maintenance of genome stability. In fact, I teach a course on maintenance of genome stability in health and disease, that’s the name of the course, and in early days, many years ago, I used to teach only about those acute diseases, the so-called genomic instability syndromes, which are terrible diseases. But these days what I tell my students is that, in fact, the problem of maintaining genomic stability is not only the problem of those patients with the rare diseases but, in fact, it is a problem of many people in the general population that suffer from a whole variety of diseases because of the fact that they do not have the ideal capacity to maintain the stability of their genome because they have this or that combination of mutations that reduce to various extents the stability of their genome.
This is also related to the way people react to therapy, specifically to cancer therapy like radiotherapy or chemotherapy. Every oncologist will tell you that different people with the same disease react tremendously differently to the same type of treatment. For example, radiotherapy, radiation, some people can tolerate the radiation doses that are given to cancer patients and they are treated successfully and some people cannot tolerate them, they develop what’s called radiation reaction. Some people can even be so badly damaged so that it will endanger their life, just the treatment. The reason is that people differ from each other in the way they respond to DNA damage and radiation treatment, of course, the most critical component in this treatment is actually the damage that is causes to the DNA, in this case the damage to the DNA is the therapy. But if people cannot tolerate those radiation doses they react very badly.
What are you currently researching?
Our research is in this field of maintenance of genomic stability. People come to this field from different areas, from different angles – cancer research, radiation oncology, other reasons. The reason we are in this field, the driving force of our research, is our interest in a genomic instability syndrome called ataxia telangiectasia, or AT for short. I became interested in AT when I was a grad student, I did my PhD thesis on AT, and later on the responsible gene was identified in our lab and we called it ATM which stands for AT mutated. It turned out that this gene encodes a very important player in DNA damage response, it’s a very powerful protein kinase called ATM that is the primary mobiliser of the complex network of responses to double strand breaks which are the most critical, most cytotoxic, DNA lesion caused by radiation, ionising radiation and radiomimetic chemicals. In fact, it is now becoming evident that ATM is involved in many other physiological processes so it is, in fact, an important homeostatic protein kinase. We’re still interested in this disease and our research actually revolves around the disease and our attempt to understand its various features, the most important of which is very severe progressive, relentless neurodegeneration which affects primarily the cerebellum.
So it is our interest in this disease, our desire to understand it and hopefully be able to contribute to finding some new treatment modalities for this disease that actually is keeping us in this field.
What is the potential for new treatment?
People are used to try to find new treatment modalities for genetic disorders ranging from enzyme therapy, gene therapy and so forth. We think that understanding the molecular pathophysiology of the disease is critical for finding new treatment modalities for this disease. That has been our approach from the start – identify the responsible gene, identify the protein, understand what the function of the missing protein is and, based on this understanding, try to understand this amazing array of symptoms of this disease which combines neurodegeneration, immune deficiency, of course genomic instability, and many other features including premature aging.
This is still our approach so we’re still studying the ATM protein, its various functions and it’s ironic that we still don’t understand completely the most important symptom of this disease which is the neurodegeneration, the cerebellar degeneration. There is actually a controversy in the field about which of the various functions of ATM is the one whose loss is responsible for this particular feature of the disease? Which is the most important feature of the disease, is the essence of this disease, because this is the symptoms that with treating makes the patient so miserable. So we’re trying to do that because we think that without understanding how the loss of ATM leads to this progressive relentless degeneration of the cerebellum and then other parts of the central nervous system we won’t be able to move forward with regard to treatment modality. So this is what we’re doing. Actually we’re doing now the same thing that I was doing as a grad student, trying to understand AT.
