Abstract
Ataxia telangiectasia mutated (ATM) is a central kinase that activates an extensive network of responses to cellular stress via a signaling role. ATM is activated by DNA double strand breaks (DSBs) and by oxidative stress, subsequently phosphorylating a plethora of target proteins. In the last several decades, newly developed molecular biological techniques have uncovered multiple roles of ATM in response to DNA damage—e.g., DSB repair, cell cycle checkpoint arrest, apoptosis, and transcription arrest. Combinational dysfunction of these stress responses impairs the accuracy of repair, consequently leading to dramatic sensitivity to ionizing radiation (IR) in ataxia telangiectasia (A-T) cells. In this review, we summarize the roles of ATM that focus on DSB repair.
Highlights
Ataxia telangiectasia (A-T) was identified as a human disorder displaying radiosensitivity at both the cellular and clinical level in 1975 [1], and was amongst the first of the DNA damage response disorders to be characterised
Dramatic sensitivity to ionising radiation (IR) and to radiomimetic drugs was evident in that first and additional early reports with cells derived from A-T individuals displaying marked sensitivity to cell killing and to chromosome aberrations, subsequent studies failed to reveal any significant defect in the repair of DNA double strand breaks (DSBs), the main lethal lesion induced by IR exposure [2]
Such a pro-non-homologous end joining (NHEJ) environment is turned into a pro-homologous recombination (HR) environment following 53BP1 dephosphorylation facilitated by breast cancer susceptibility protein 1 (BRCA1)-protein phosphatase 4 catalytic subunit (PP4C) in S/G2 phase [51] (Figure 4)
Summary
Ataxia telangiectasia (A-T) was identified as a human disorder displaying radiosensitivity at both the cellular and clinical level in 1975 [1], and was amongst the first of the DNA damage response disorders to be characterised. ATM was shown to be a protein kinase rather than a lipid kinase and classified as a PI3K-like kinase (PIKK) These important findings helped to explain the broad phenotypes of A-T cells and the diverse clinical manifestation of the disorder. The co-ordination of these responses optimises the repair of DSBs in the context of chromatin structure and the interface with other DNA metabolic processes, such as transcription. Failure to initiate this broad range of responses impacts upon DSB repair in complex ways, which we detail here. We will evaluate how these defects might contribute to the clinical manifestation of A-T
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