The function of the ATM protein
The ATM protein is of a type called a ‘kinase’, a protein which plays a role in triggering or blocking the activity of other proteins in cellular processes. You may hear the phrase ‘kinase activity’ to describe this. For example in people with classic A-T there is ‘no kinase activity’ – either no ATM protein is produced or if one is, then it is not active. By contrast, people with variant A-T will have some limited kinase activity.
The problem for researchers, is that ATM is a very important and active protein, interacting with many hundreds of other proteins in cells. So far nearly 1000 cells that interact with ATM have been identified. This means that there are a large number of processes that are affected by its absence.
While ATM is clearly very important, many cells seem to be able to work fine without it. People with A-T have no problems thinking, or hearing and all their organs seem to work pretty well. What we don’t understand is, why some cells, for example those in the cerebellum, don’t function well and indeed gradually die off. Is there a particular function of ATM that when absent causes cells in the cerebellum to die, when other brain cells don’t? If we knew this, we might be able to intervene to restore that process and keep the cells alive. There have been a number of different theories, but as yet, we don’t know the answer. Below we look at some of the most important roles of ATM.
This is the best-known function of ATM. The DNA in all the cells of your body is being copied constantly, whether to create new proteins or to reproduce cells. Sometimes the DNA gets damaged. For example, the strands of DNA may break, the copying may get garbled or there might be damage from outside sources such as radiation or viruses. If this damaged DNA is copied, it can cause problems, potentially giving rise to conditions like cancer. It is estimated that in a single human, DNA is damaged around two trillion times a day (that’s 2,000,000,000,000,000,000!).
To deal with this, cells have processes to identify when DNA has been damaged and then if possible repair the damage, and if not, kill the cell so that the mistake can’t be replicated. ATM has a central role in this. It plays a key role in identifying that damage has been done and in recruiting other molecules to the site to start the repair process. It should be underlined though that these process are extremely complex, involving over 500 different proteins
Most cases involve damage to one of the two strands of DNA. These single-strand breaks (SSBs) are easier to repair, as you can use the other strand as a template. However, more rarely but more dangerously, both strands are damaged or broken – double-strand breaks (DSBs).
It is known that ATM plays a key role in repairing DSBs. This is the reason why people with A-T are sensitive to radiation and x-rays, as these tend to cause DSBs, which cannot then be easily repaired, leading to cells dying off. There is less clear evidence about its role in dealing with the much more common SSBs.
It appears that it is this function of ATM which is responsible for immunodeficiency in A-T. Part of the process of creating antibodies involves putting together different sections of DNA, in a process called ‘V(D)J recombination’. ATM plays a significant role in this and in its absence the process is clearly much less efficient.
In the course of normal cell processes, damaging chemicals called ‘reactive oxygen species’ or ‘free radicals’ are formed. Cells have processes in place to deal with these but if these processes are inefficient or as a result of external stimuli (e.g. radiation, pollution or smoke) these free radicals can build up and start to damage the cell and its processes and also lead to DNA damage. This state is called oxidative stress. ATM is known to be activated by oxidative stress, and clearly plays an important role in these processes.
Telomeres are lengths of ‘spare’ DNA at the end of chromosomes, which protect the important DNA when the chromosome is copied – otherwise information at the end of the chromosome is likely to be lost. Over time the telomeres themselves become shorter. In the absence of ATM it appears that telomeres are shortened and this may be the reason for some of the premature aging features of A-T.