DNA Damage Response as a Pharmacological Target for Cancer and Infectious Diseases

Poplawski, Tomasz
Current Medicinal Chemistry, 26(8): 1423—1424, 2019

Maintaining genome integrity is crucial for all cells due to the central role of DNA in heredity and gene expression. It is a very challenging task as every cell must deal with over 70,000 DNA lesions daily. There are two groups of DNA damage sources – endogenous (cellular) and exogenous (environmental). Both of them can result in similar types of DNA lesions and contribute significantly to DNA instability. Thus, it is no surprise that cells evolved a mechanism to deal with DNA damage. This mechanism is limited not only to DNA repair per se but also include other cellular events like DNA damage recognition and intracellular signaling with checkpoints, signal transduction and effector systems. All these events, taken together are known as DNA damage response (DDR). Given DDR importance, the scientists have tried to interrupt the DDR to effectively kill “bad” cells including cancer and human pathogens. Although the first DDR-orientated therapy utilized O6-methylguanine-DNA methyltransferase inhibitors, the clinical success of PARP inhibitors in cancer treatment (exploiting the phenomenon of synthetic lethality) showed the great potential of DDR inhibitors. Nowadays, there are two main trends in the development of DDR-inhibitors-searching for novel examples of synthetic lethality and molecular targets within DDR and synthesis of novel DDR inhibitors. Growing evidence suggests that DDR-orientated therapy would work well not only in cancer but also in infection diseases including mycobacteria.