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ATM and related protein kinases: safeguarding genome integrity

Key Points

  • The DNA-damage response is crucial for cellular life and for avoiding neoplasia. It occurs by rapidly transducing the damage signal to many cellular systems, such as the DNA-repair machinery and the cell-cycle checkpoints.

  • Double-strand breaks (DSBs) in the DNA — deadly DNA lesions — mobilize an intricate signalling network by activating the ATM protein kinase, which, in turn, orchestrates this network by phosphorylating one or more key proteins in each of its branches.

  • Other protein kinases related to ATM carry out similar functions in response to other genotoxic stresses, and some of them collaborate with ATM in the DSB response.

  • ATM deficiency leads to ataxia-telangiectasia (A-T), a genomic instability syndrome, the hallmarks of which — neurodegeneration, immunodeficiency, radiation sensitivity and cancer predisposition — show the intimate connection between maintenance of genome stability, cellular and tissue functioning, and cancer prevention.

  • Certain types of ATM mutations seem to increase cancer predisposition in heterozygous carriers. This adds ATM to the list of genes that have sequence variations with important implications for public health, especially with regards to cancer epidemiology.

Abstract

Maintenance of genome stability is essential for avoiding the passage to neoplasia. The DNA-damage response — a cornerstone of genome stability — occurs by a swift transduction of the DNA-damage signal to many cellular pathways. A prime example is the cellular response to DNA double-strand breaks, which activate the ATM protein kinase that, in turn, modulates numerous signalling pathways. ATM mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia (A-T). Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.

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Figure 1: Cellular responses to DNA damage.
Figure 2: Basic steps in a current model of the cellular survival response to DSBs.
Figure 3: Size and common motifs in the human members of the PIKK family.
Figure 4: ATM-mediated activation of cell-cycle checkpoints in response to DSBs.

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Acknowledgements

The author wishes to thank the members of the David and Inez Myers Laboratory for Genetic Research for their dedication to A-T research. Work in the author's laboratory is supported by research grants from the A-T Medical Research Foundation, The A-T Children's Project, The A-T Medical Research Trust, The National Institutes of Health and the Israel Ministry of Science, Culture and Sport.

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DATABASES

LocusLink

53BP1

ABL

ATM

ATRIP

ATR

ATX

BLM

BRCA1

BRCA2

CDC25A

CDC25C

CDK2

CHK1

cyclin E

E2F1

FANCD2

H2AX

KU70

KU80

MDM2

MRE11

mTOR

NBS1

NF-κB

p53

PI3K

RAD9

RAD17

RAD50

RAD51

RAD52

RAD54

SMC1

TRF1

TRRAP

WAF1

OMIM

ataxia telangiectasia

Bloom's syndrome

Fanconi's anaemia

Nijmegen breakage syndrome

FURTHER INFORMATION

The ATM entry in the NCBI web site

Information on A-T at the NIH site

Glossary

CELL-CYCLE CHECKPOINTS

Regulatory mechanisms that do not allow the initiation of a new phase of the cell cycle before the previous one is completed, or temporarily arrest cell-cycle progression in response to stress. DNA damage activates specific checkpoints at the G1–S and G2–M boundaries and in the S phase, with each one based on a different mechanism.

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Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer 3, 155–168 (2003). https://doi.org/10.1038/nrc1011

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