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Cellular functions of the protein kinase ATM and their relevance to human disease

Abstract

The protein kinase ataxia telangiectasia mutated (ATM) is a master regulator of double-strand DNA break (DSB) signalling and stress responses. For three decades, ATM has been investigated extensively to elucidate its roles in the DNA damage response (DDR) and in the pathogenesis of ataxia telangiectasia (A-T), a human neurodegenerative disease caused by loss of ATM. Although hundreds of proteins have been identified as ATM phosphorylation targets and many important roles for this kinase have been identified, it is still unclear how ATM deficiency leads to the early-onset cerebellar degeneration that is common in all individuals with A-T. Recent studies suggest the existence of links between ATM deficiency and other cerebellum-specific neurological disorders, as well as the existence of broader similarities with more common neurodegenerative disorders. In this Review, we discuss recent structural insights into ATM regulation, and possible aetiologies of A-T phenotypes, including reactive oxygen species, mitochondrial dysfunction, alterations in transcription, R-loop metabolism and alternative splicing, defects in cellular proteostasis and metabolism, and potential pathogenic roles for hyper-poly(ADP-ribosyl)ation.

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Fig. 1: Known ATM activation mechanisms.
Fig. 2: ATM structure.
Fig. 3: A subset of the roles for ATM in DNA repair.
Fig. 4: Roles for ATM in redox homeostasis and consequences of the loss of this function in mitochondria.
Fig. 5: PARP hyperactivity in the absence of ATM.
Fig. 6: Model of ataxia telangiectasia pathogenesis.

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Acknowledgements

The authors thank P. McKinnon and V. Costanzo for comments on the manuscript. The original figures were generated with the assistance of BioRender.

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Glossary

Topoisomerase cleavage complexes

TOP1 or TOP2 covalent intermediates, in which the enzymes are linked to DNA through the catalytic tyrosine residue; stabilized by topoisomerase poisons, some of which are used in cancer therapy.

R-loops

Three-stranded nucleic acid structures composed of a DNA–RNA hybrid and the associated non-template single-stranded DNA.

HEAT repeats

(Huntingtin, elongation factor 3, A subunit of protein phosphatase 2A, TOR1). Antiparallel helices linked by a flexible loop; often occur in series.

RAD51 filament

Refers to RAD51 proteins assembled on and coating single-stranded DNA.

Intrinsically disordered regions

(IDRs). Protein domains that lack easily definable structure, sometimes associated with low sequence complexity. IDRs can acquire order in the presence of other proteins or nucleic acids.

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Lee, JH., Paull, T.T. Cellular functions of the protein kinase ATM and their relevance to human disease. Nat Rev Mol Cell Biol 22, 796–814 (2021). https://doi.org/10.1038/s41580-021-00394-2

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