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Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer

Nature Reviews Molecular Cell Biology volume 9, pages 759–769 (2008)Cite this article

A Corrigendum to this article was published on 01 December 2008

Key Points

  • Ataxia-telangiectasia (A-T) is a rare human genetic disorder that is characterized by cancer predisposition, neurodegeneration, immunodeficiency, radiosensitivity, chromosomal instability and cell-cycle checkpoint defects.

  • A-T mutated (ATM) protein is a member of the phosphoinositide 3-kinase (PI3K)-related protein kinase (PIKK) family of protein kinases and has a central role in the response to DNA double-strand breaks (DSBs).

  • ATM responds to breaks introduced by DNA-damaging agents and to physiologically induced breaks.

  • ATM is activated by dissociation of an inactive dimer to form an active monomeric form of the protein.

  • Autophosphorylation and acetylation contribute to ATM activation.

  • Partial activation of ATM occurs in response to agents that alter chromatin structure, and full activation is achieved when it is recruited to the MRE11–RAD50–NBS1 (MRN) complex at the break site.

  • Recruitment of ATM to a DNA DSB occurs as part of an assembly complex with other proteins, including H2AX, MDC1, RNF8 and BRCA1.

  • The MRN complex assists in the activation of ATM and in time becomes a substrate (through NBS1) for active ATM.

  • Once activated, ATM phosphorylates a multitude of substrates that are involved in cell-cycle checkpoint activation and DNA repair. The MRN complex has an adaptor role, at least in the case of some of these substrates.

Abstract

First described over 80 years ago, ataxia-telangiectasia (A-T) was defined as a clinical entity 50 years ago. Although not encountered by most clinicians, it is a paradigm for cancer predisposition and neurodegenerative disorders and has a central role in our understanding of the DNA-damage response, signal transduction and cell-cycle control. The discovery of the protein A-T mutated (ATM) that is deficient in A-T paved the way for rapid progress on understanding how ATM functions with a host of other proteins to protect against genome instability and reduce the risk of cancer and other pathologies.

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Figure 1: Activation of ATM.
Figure 2: The MRN complex tethers DNA broken ends.
Figure 3: Assembly of DNA-damage response proteins at a double-strand break.
Figure 4: ATM activation and signalling to downstream substrates in response to DNA double-strand breaks.

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  1. Radiation Biology and Oncology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia and the University of Queensland, Centre for Clinical Research, Brisbane, QLD 4029, Australia. martin.lavin@qimr.edu.au,

    Martin F. Lavin

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Glossary

Checkpoint

In this example, a cell-cycle checkpoint is a control mechanism to ensure that chromosomes are intact for cell division.

Adaptor

A protein that assists in the process of downstream signalling. In this case, NBS1 has an adaptor role in ATM signalling.

Radioresistant DNA synthesis

The absence of a steep component of inhibition of DNA synthesis in a dose–response curve when the rate of DNA synthesis is plotted against radiation doses.

Complementation group

This refers to previous studies on A-T cells in which cell fusion was used to determine whether more than one protein was involved in the defect.

Non-homologous end joining (NHEJ) repair

The repair of DNA double-strand breaks (free ends) by DNA-PK and other cofactors without the requirement for DNA recombination.

Heterochromatin

A cytologically distinct, tightly packed form of chromatin in which transcription is repressed.

V(D)J recombination

A mechanism that involves gene rearrangement in the maturation of immunoglobulin and T-cell receptor genes.

Peroxisomes

Subcellular organelles that metabolize fatty acids and clear the cell of toxic peroxides.

Endosomes

Vesicles derived from the plasma membrane to transport proteins and other substances into the cell.

Purkinje cell

Neuronal cells found on the cerebellum between the molecular and granular layers.

Autophosphorylation

The process by which a protein kinase uses itself as a substrate for phosphorylation in many cases for self-activation.

Downstream signalling

Part of a signal transduction pathway in which a protein, such as ATM, phosphorylates a series of substrates that assist in controlling various cellular processes.

FHA domain

(Forkhead-associated domain). A short sequence of amino acids that binds to phosphothreonine residues on various proteins.

ATPase domain

The region of a protein that is responsible for the hydrolysis of ATP and is coupled to protein phosphorylation.

Exonuclease

The enzyme that degrades nucleic acids from 3′ to 5′ free ends.

Endonuclease

An enzyme that is capable of hydrolysing phosphodiester bonds in nucleic acids that are away from the free ends.

Ubiquitylation

Post-translational modification of a protein by the covalent attachment of a ubiquitin protein to enable degradation or other forms of regulation.

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Lavin, M. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9, 759–769 (2008). https://doi.org/10.1038/nrm2514

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