A number of articles have been circulating in recent days about a scientific paper which gives new insights into the role of ATM in repairing damage to DNA. The articles suggest that this discovery may help with the ‘development of new therapies’ for A-T and similar conditions. What many people living with A-T will want to know is is how big a step forward this actually is.
Many people with an interest in A-T will be aware that the ATM protein (which is missing in people with A-T) is involved in repairing “double-strand” breaks to DNA – this is when both the strands of the ‘double helix’ which makes up DNA are broken. However, while double-strand breaks occur regularly, they are much less common than single-strand breaks, which occur thousands of times a day in every cell and are normally repaired quickly and efficiently.
What is new in this paper by Khoronenkova and Dianov (PNAS, 2014) is that it provides evidence that ATM is also activated by single-strand breaks. However, rather than contributing directly to repairing the breaks, it seems that the way ATM works is to slow down the cycle by which the cell reproduces itself. This gives extra time for the single-strand breaks to be repaired before the reproduction process, where there is a risk that they may turn into more serious double-strand breaks.
One of the problems we face in treating A-T is that ATM has many linked roles in the cell, and we do not understand which of the many roles is most critical because of a lack of ATM which causes the symptoms of A-T. This new finding is very interesting because the progressive ataxia which affects A–T patients is a feature that occurs in other syndromes with defects in single-strand rather than double-strand repair. This suggests that it may be this function which is critical.
However, there are still serious questions to answer. The brain cells (neurons) affected in A-T are predominantly non-replicating. So it is not clear why the loss of ATM should have such an impact and lead to neurodegeneration if the role of ATM is to slow down the replication process.
It is noteworthy that Peter McKinnon’s laboratory in the USA has reported that ATM has a role in the repair of a type of single-strand break. However, this method of ATM activation appears to occur by a distinctly different process.
In conclusion, the study is significant in providing evidence that ATM can become activated when only single strand breaks are present. However, further work is required to investigate whether this novel role of ATM underlies the ataxia and whether it can be exploited to develop new treatments.