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The ATM protein kinase: regulating the cellular response to genotoxic stress, and more

Key Points

  • ATM is a powerful protein kinase, the function of which is lost in patients with the genomic instability syndrome ataxia-telangiectasia.

  • The most documented function of ATM is mobilizing and regulating the cellular response to DNA double-strand breaks (DSBs).

  • ATM is a member of the PIKK (PI3K-like protein kinase) family and has functional relationships with two other PIKKs, ATR (ATM and RAD3-related) and DNA-PKcs (DNA-dependent protein kinase catalytic subunit), which are involved in the cellular response to genotoxic stress.

  • ATM is vigorously activated following DSB induction and firmly controls but also fine-tunes a complex signalling network by phosphorylating a multitude of substrates in numerous branches and control layers of this network.

  • Our view of ATM is becoming broader in light of evidence of its function in responses to other genotoxic stresses and in various branches of metabolism and cell signalling.

  • ATM is taking on the new image of a homeostatic protein kinase that exhibits exceptional versatility as a player that responds vigorously to DSBs by taking charge of the vast DSB-response network.

Abstract

The protein kinase ataxia-telangiectasia mutated (ATM) is best known for its role as an apical activator of the DNA damage response in the face of DNA double-strand breaks (DSBs). Following induction of DSBs, ATM mobilizes one of the most extensive signalling networks that responds to specific stimuli and modifies directly or indirectly a broad range of targets. Although most ATM research has focused on this function, evidence suggests that ATM-mediated phosphorylation has a role in the response to other types of genotoxic stress. Moreover, it has become apparent that ATM is active in other cell signalling pathways involved in maintaining cellular homeostasis.

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Figure 1: The DDR cascade and ATM.
Figure 2: The scope of the ATM-mediated DNA damage response.
Figure 3: ATM-mediated activation and stabilization of p53 in response to DNA damage induction.
Figure 4: Involvement of ATM in cellular homeostasis pathways.

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Acknowledgements

The authors thank Z.-Q Wang, C. Bakkenist, A. Gross, A. Barzilai, M. Lavin, S. El-Khamisy, H. Sharfi, D. Delia, A. Bensimon, R. Jachimowicz, R. Elkon and the members of The David and Inez Myers Laboratory for Cancer Genetics for very useful comments, A. Paz and G. Mass for data management and creative artwork, and F. Zetland for editing the manuscript. Work in the authors laboratory is supported by the David and Inez Myers Foundation, the Ataxia-Telangiectasia (A-T) Medical Research Foundation, the Israel Science Foundation, the A-T Ease Foundation, the Israel Cancer Research Fund, the German–Israeli Foundation for Scientific Research and Development, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Israeli Centers for Research Excellence (I-CORE) Program of the Planning and Budgeting Committee and the Israel Science Foundation. Y.S. is a Research Professor of the Israel Cancer Research Fund.

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FURTHER INFORMATION

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Leiden Open Variation Database

Signaling Pathway Integrated Knowledge Engine (SPIKE)

Gene Ontology

Glossary

Fanconi anaemia pathway

A DNA damage response pathway that responds predominantly to DNA interstrand crosslinks. Mutations leading to loss of any of the15 proteins in this pathway cause the genomic instability syndrome Fanconi anaemia in humans.

DNA crosslink

Covalent linkage of two positions in the DNA molecule (in the same strand or in opposite strands), caused by endogenous or exogenous bifunctional agents that interact with both positions.

Replication stress

Stress on DNA metabolism imposed by inefficient DNA replication that leads to slowing or stalling of replication forks. It can be caused by DNA damage, depletion of dNTP pools or decreased or extremely increased replicon initiation.

Hypotonic stress

Stress on cellular homeostasis imposed by a hypotonic environment in which the extracellular solute concentration is lower than the intracellular one. Osmosis then causes a flow of water into the cell, compromising its integrity.

Kinetochore

A multiprotein complex that assembles on centromeric DNA. It mediates the attachment of chromosomes to spindle fibres and their subsequent movement to the mitotic spindle poles.

Apolipoprotein E

(APOE). A class of apolipoprotein that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. APOE transports lipoproteins, fat-soluble vitamins and cholesterol into the lymphatic system and then into the blood.

Reactive oxygen species

(ROS). Important signalling intermediates with special roles in stem cell renewal and apoptosis. They are byproducts of cellular metabolism that also pose a constant threat to cellular constituents. Excess ROS or other oxidants beyond the cellular antioxidant capacity leads to oxidative stress, with broad pathological consequences.

Pentose phosphate cycle

A cytoplasmic chain of reactions that oxidizes glucose, reduces NADP to NADPH and generates pentoses (5-carbon sugars). It is the major source of the NADPH required for anabolic processes.

Autophagy

A tightly regulated catabolic process involving degradation of cellular components through the lysosomal machinery. During steady-state conditions, it maintains homeostasis through the elimination of damaged organelles and proteins. Under stress conditions, such as nutrient starvation, it is highly enhanced, reallocating nutrients from less essential processes to crucial ones and providing the cell with building blocks for survival.

Thymocytes

Haematopoietic progenitor cells that are present in the thymus. They differentiate into mature T cells.

Nigrostriatal pathway

A neural pathway that connects two areas in the brain, the substantia nigra and the striatum. It is one of the four major dopaminergic pathways in the brain and is involved in the production of movement.

Dopaminergic neurons

The main source of dopamine in the mammalian central nervous system. Their loss is associated with Parkinson's disease and various mood disorders.

Hippocampal neurons

Cells of the cerebral cortex that are involved in memory formation, consolidation, indexing and storage, as well as spatial orientation and navigation.

Neural network

Circuits based on groups of neurons and glial cells that are connected or functionally related and together perform a specific physiological function.

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Shiloh, Y., Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14, 197–210 (2013). https://doi.org/10.1038/nrm3546

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