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ATM: a mediator of multiple responses to genotoxic stress
1Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
Abstract:
The ATM protein kinase is the product of the gene responsible for the pleiotropic recessive disorder ataxia-telangiectasia. ATM-deficient cells show enhanced sensitivity and greatly reduced responses to genotoxic agents that generate DNA double strand breaks (DSBs), such as ionizing radiation and radiomimetic chemicals, but exhibit normal responses to DNA adducts and base modifications induced by other agents. Therefore, DSBs are most likely the predominant signal for the activation of ATM-mediated pathways. Identification of the ATM gene triggered extensive research aimed at elucidating the numerous functions of its large multifaceted protein product. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in the nucleus where it plays a central role in the very early stages of damage detection and serves as a master controller of cellular responses to DSBs. By activating key regulators of multiple signal transduction pathways, ATM mediates the efficient induction of a signaling network responsible for repair of the damage, and for cellular recovery and survival.
Insights
Ataxia-telangiectasia mutated (ATM) protein kinase is crucial for detecting DNA double-strand breaks (DSBs). ATM activation orchestrates cellular repair and survival pathways following DNA damage.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Ataxia-telangiectasia is a pleiotropic recessive disorder caused by mutations in the ATM gene.
- ATM-deficient cells exhibit hypersensitivity and impaired responses to DNA double-strand breaks (DSBs).
- ATM's primary role appears to be signaling in response to DSBs, rather than other DNA lesions.
Purpose of the Study:
- To review the nuclear functions of the ATM protein kinase.
- To elucidate ATM's role as a master controller in cellular responses to DSBs.
- To highlight ATM's function in initiating DNA damage detection and repair signaling.
Main Methods:
- Literature review focusing on ATM's nuclear functions.
- Analysis of cellular responses to genotoxic agents inducing DSBs.
- Examination of ATM's role in signal transduction pathways.
Main Results:
- ATM is activated predominantly by DSBs, acting as an early damage sensor.
- ATM plays a central role in the nucleus, controlling cellular responses to DSBs.
- ATM activates key regulators, initiating signaling networks for DNA repair and cell survival.
Conclusions:
- ATM is a critical mediator of cellular responses to DNA double-strand breaks.
- ATM's nuclear functions are essential for DNA damage detection, repair, and cell survival.
- Understanding ATM pathways is key to addressing disorders like ataxia-telangiectasia.