Innovators in DNA Repair and Synthetic Lethality
The 2015 Nobel Prize in Chemistry was awarded for work on the mechanisms of DNA repair and their importance in human physiology.
There are around 30 trillion cells in the human body, each of which contains 6.4 billion base-pairs of DNA. It is estimated that each of the 30 trillion cells suffers up to a million individual DNA damage events per day. Consequently humans have evolved highly powerful systems to repair this daily barrage of DNA damage, and keep healthy cells functioning correctly and efficiently. The abnormal cells that cause diseases such as cancer or autoimmunity also rely on DNA repair, but the normal repair systems are often corrupted in these diseases. This creates a critical weakness in cancer and autoimmune disease that can be exploited by targeting the abnormal DNA repair.
Normal cells experience sporadic DNA damage and have multiple repair systems with fail-safe redundancies. Diseased cells undergo significantly more DNA damage, nearly to the limit of their repair capacity. DNA damage that escapes repair can lead to mutations which, in turn, can exacerbate the disease. By therapeutically targeting DNA repair, diseased cells – but not healthy normal cells – become overloaded with DNA damage, and self-destruct.
Synthetic lethality is a phenomenon, first discovered in genetic model systems, in which two genetic dysfunctions – neither of which is detrimental on its own – combine to kill a cell.
The first synthetic lethal interactions discovered were caused by mutations that resulted in loss of activity in the gene pairs. An example of this loss-of-function type of synthetic lethality occurs with BRCA1/2 mutations and the DNA repair factor PARP. This biology has been the focus of intense pharmaceutical interest, with one approved PARP inhibitor and several more in development for use as synthetic lethal therapies in BRCA defective breast and ovarian cancers.
Our scientists have discovered a new type of synthetic lethality, based on genetic gains-of-function. Cancers and many autoimmune diseases acquire new genetic features that do not exist in normal, healthy cells or tissues. Many of these genetic gains-of-function – for example, in oncogenes that drive cancer – lead to excessive DNA damage. Cyteir is developing a new generation of novel synthetic lethal therapies that target these gain-of-function events.