The ATM signaling network in development and disease

Abstract

The DNA damage response (DDR) rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence (Jackson and Bartek, 2009). DNA double-strand breaks (DSBs) represent one of the most cytotoxic DNA lesions and defects in their metabolism underlie many human hereditary diseases characterized by genomic instability (Stracker and Petrini, 2011; McKinnon, 2012). Patients with hereditary defects in the DDR display defects in development, particularly affecting the central nervous system, the immune system and the germline, as well as aberrant metabolic regulation and cancer predisposition. Central to the DDR to DSBs is the ataxia-telangiectasia mutated (ATM) kinase, a master controller of signal transduction. Understanding how ATM signaling regulates various aspects of the DDR and its roles in vivo is critical for our understanding of human disease, its diagnosis and its treatment. This review will describe the general roles of ATM signaling and highlight some recent advances that have shed light on the diverse roles of ATM and related proteins in human disease.

Predictability, efficacy and safety of radiosensitization of glioblastoma-initiating cells by the ATM inhibitor KU-60019

“…Although this aspect certainly requires further studies, it might be possible that an aberrant, mutagenic DDR exists in COMI or that the radiosensitization exerted by KU-60019 synergizes with ouabain toxicity, with preferential elimination of KU-60019-treated mutant clones. 8 In vivo, because it is not known to what extent KU-60019 crosses the brain-blood barrier, increasing concentrations of the drug were administered intracranially. Three different delivery procedures were used, namely direct injection, osmotic mini-pumps and reabsorbable clots.…”

NBS1 is required for macrophage homeostasis and functional activity in mice

“…7,8 Mutations in any MRE11 complex members or ATM underlies rare genetic instability syndromes with overlapping pathologies that affect the central nervous system, germline, and immune system. 4,7 NBS1 mutations cause Nijmegen breakage syndrome (NBS), 7,9,10 characterized by microcephaly, growth and mental retardation, immunodeficiency, and predisposition to cancer. 11 This syndrome highlights the importance of the DDR in the development and function of the central nervous and immune systems.…”

“…2,3 The MRE11 complex, composed of meiotic recombination 11 homolog (MRE11), Nijmegen breakage syndrome 1 (NBS1), and RAD50, is a DSB sensor that regulates the DNA damage response (DDR) and repair of DSBs. 4 Break detection by the MRE11 complex activates the ataxia telangiectasia mutated (ATM) kinase that promotes a robust DDR that includes the activation of checkpoint kinase 2 (CHK2) and the tumor suppressor p53. 5 NBS1 has no identifiable enzymatic activities and appears to function primarily as an adaptor protein required for MRE11 complex nuclear localization.…”

Cancer stem cells and addicted cancer cells

“…Mutations in genes that are involved in the regulation of these checkpoints are often present in cancer cells, such as tumor suppressor gene P53 and ATM. ATM codes for ataxia-telangiectasia kinase that phosphorylates proteins in response to cellular stresses, leading the activation of cell cycle checkpoints and consequently to cell cycle arrest, DNA repair or apoptosis [31]. Defects in these genes can also result in a selective growth advantage by allowing cells with chromosomal alterations that favor growth to survive and divide.…”