ATM: Its Recruitment, Activation, Signalling and Contribution to Tumour Suppression

Abstract

DNA double strand breaks (DSBs) are a critical lesion for cancer etiology. Most cancer cells incur increased DNA breakage to enhance genomic instability. The DSB damage response encompasses pathways of repair and a signal transduction pathway. The ataxia telangiectasia mutated (ATM) kinase lies at the centre of the signalling response. ATM is not essential for the major DSB repair process in mammalian cells but influences DSB repair, including its accuracy, in multiple ways. ATM is activated by DSBs to promote cell cycle checkpoint arrest and apoptosis. There is mounting evidence that ATM is active endogenously and/or that it can be activated by non-DSB routes, including oxidative damage. It plays an important role in regulating cellular redox status. The tumour suppressor functions of ATM are discussed. Paradoxically, since elevated DSBs arise in cancer cells, despite being a tumour suppressor, pharmacological inhibition of ATM is a promising route for cancer therapy.