The many substrates and functions of ATM

Abstract

As its name suggests, the ATM ? 'ataxia-telangiectasia, mutated' ? gene is responsible for the rare disorder ataxia-telangiectasia. Patients show various abnormalities, mainly in their responses to DNA damage, but also in other cellular processes. Although it is hard to understand how a single gene product is involved in so many physiological processes, a clear picture is starting to emerge.

Key Points

online summary

  • Ataxia-telangiectasia, mutated (ATM) is the gene responsible for the rare disorder ataxia-telangiectasia. Patients show abnormalities mainly in their response to DNA damage.

  • ATM acts specifically in the cellular response to ionizing radiation and DNA double-stranded breaks (DSBs).

  • ATM differs from other similar DNA-repair enzymes (ATR and DNA-PK) in that its activity does not depend on manganese and, unlike DNA-PK, it is not clear that the activity of ATM is directly activated by DNA ends.

  • The cell-cycle checkpoint responses at G1, S and G2 are all markedly abnormal in ATM-deficient cells.

  • ATM is proposed to regulate the G1 checkpoint through indirect regulation of p53. Evidence indicates that ATM phosphorylates another kinase CHK2, which in turn phosphorylates p53. This disrupts the interaction between p53 and MDM2, and so induces a G1 checkpoint.

  • ATM controls the S-phase checkpoint through phosphorylation of NBS1, which localizes in a complex that is recruited to DSBs. Other proteins in this complex are also possible targets.

  • None of the proteins that regulates the G2?M checkpoint has been identified as an ATM target. Evidence is discussed in support of coordination between two candidates ? CHK1 and CHK2 ? which are phosphorylated by ATR and ATM, respectively. BRCA1, which is phosphorylated by both ATM and CHK2, is also implicated.

  • ATM-deficient cells show abnormal DSB repair. This may be due to abnormal chromatin remodelling; this is supported by the observation that ATM binds to the chromatin-remodelling enzyme histone deacetylase. ATM is also required for homologous recombination, one of the pathways that functions to repair DSBs.

  • Patients with ataxia telangiectasia also have abnormal nervous-system development and insulin signalling. It is not clear whether the defects observed in these patients are due just to a loss of DSB repair in these tissues or whether ATM functions in other signalling pathways here.

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Figure 1: Function of ATM in cell-cycle checkpoints and DNA repair pathways.
Figure 2: ATM and other molecular signals controlling cell-cycle checkpoints after ionizing radiation.
Figure 3: A role of ATM in DNA double-stranded break repair pathways.

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Correspondence to Michael B. Kastan.

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DATABASE LINKS

Ataxia-telangiectasia

ATM

PI(3)K

MTOR

DNA-PK

p53

KU70

KU80

RPA

ATR

p21

CDK2

p300

MDM2

CHK2

NBS1

Nijmegen breakage syndrome

RAD50

MRE11

ataxia-telangiectasia-like disorder

BRCA1

CDC25

CHK1

MSH2

MSH6

MLH

BLM

ligase IV

c-Abl

NF-κB

β-adaptin

4E-BP1

Glossary

REPLICATION PROTEIN A

A single-stranded DNA-binding factor that is essential for DNA repair, recombination and replication.

V(D)J RECOMBINATION

A specialized form of recombination that assembles the genes that encode lymphocyte antigen receptors from variable (V), diversity (D) and joining (J) gene segments. DNA double-strand breaks are introduced between the V, D and J segments and DNA repair proteins then join the segments together.

CHK2

A serine/threonine protein kinase that has an important function in cell-cycle regulation in response to DNA damage.

RADIORESISTANT DNA SYNTHESIS

A failure of the rapid decrease in DNA synthesis in ataxia-telangiectasia cells that occurs in normal cells after ionizing radiation.

RESTRICTION POINT

A point late in the G1 stage of the cell cycle at which mammalian cells become committed to entry into S phase, even without other growth factors.

REPLICON

A structural complex at which replication of DNA occurs.

HYDROXYUREA

A inhibitor of ribonucleotide reductase that blocks replication during S phase by preventing nucleotide synthesis.

MICROCEPHALY

An abnormally small head.

ATAXIA

Dyscoordination of gait and other movements controlled by cerebellum.

BRCA1

A tumour-suppressor gene that is linked to hereditary early onset of breast and ovarian cancer.

PROPIDIUM IODIDE ASSAY

A fluorescent DNA-intercalating dye used to measure DNA content in flow cytometry assays.

14-3-3 PROTEIN

A regulatory protein that binds to phosphorylated forms of various proteins that are involved in signal transduction and cell-cycle control.

BLASTOCYST

An early stage of embryonic development at which cells begin to commit to certain developmental lineages.

HISTONE DEACETYLASE

An enzyme that removes the acetyl groups of core histones; its activity has an important function in transcriptional regulation and cell-cycle progression through alterations in chromatin structure.

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Kastan, M., Lim, Ds. The many substrates and functions of ATM. Nat Rev Mol Cell Biol 1, 179–186 (2000). https://doi.org/10.1038/35043058

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