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ATR: an essential regulator of genome integrity

Key Points

  • Ataxia-telangiectasia mutated (ATM) and RAD3-related (ATR) is a member of the phosphoinositide 3-kinase (PI3K)-related family of protein kinases, which includes ATM, that regulates DNA-damage responses to maintain genome integrity.

  • A common DNA structure — single-stranded DNA (ssDNA) with a 5′ double-stranded primer junction — is responsible in most instances for ATR activation.

  • ATR binds to a protein cofactor, ATR-interacting protein (ATRIP), that regulates ATR localization and activation.

  • Topoisomerase-binding protein-1 (TOPBP1) directly activates ATR–ATRIP complexes. Its recruitment to DNA lesions is promoted by the 9-1-1 checkpoint clamp.

  • ATR signals to regulate DNA replication, cell-cycle transitions and DNA repair through the phosphorylation of hundreds of substrates, including checkpoint kinase-1 (CHK1) and the minichromosome maintenance (MCM) helicase complex.

  • ATM and ATR have overlapping but non-redundant functions in the DNA-damage response. Crosstalk between these pathways often occurs as a consequence of interconversion of the activating DNA lesions.

  • ATR is essential for the survival of most replicating cells, perhaps because of the ubiquitous presence of DNA lesions and replication stress.

Abstract

Genome maintenance is a constant concern for cells, and a coordinated response to DNA damage is required to maintain cellular viability and prevent disease. The ataxia-telangiectasia mutated (ATM) and ATM and RAD3-related (ATR) protein kinases act as master regulators of the DNA-damage response by signalling to control cell-cycle transitions, DNA replication, DNA repair and apoptosis. Recent studies have provided new insights into the mechanisms that control ATR activation, have helped to explain the overlapping but non-redundant activities of ATR and ATM in DNA-damage signalling, and have clarified the crucial functions of ATR in maintaining genome integrity.

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Figure 1: Simple models for ATR and ATM activation.
Figure 2: A common DNA structure activates ATR.
Figure 3: ATR phosphorylates numerous substrates to regulate replication and cell-cycle transitions.
Figure 4: Interconversion of ATR- and ATM-activating DNA lesions.

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Acknowledgements

Research in the Cimprich laboratory is supported by the National Institute of Environmental Health Sciences, the American Cancer Society and the California Breast Cancer Research Program. K.A.C. is a Leukemia and Lymphoma Scholar. The Cortez laboratory is supported by the National Cancer Institute, the Robert J. Kleberg Jr and Helen C. Kleberg Foundation and the Ingram Charitable Fund. The authors apologize for the many important references that could not be discussed owing to space limitations.

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DATABASES

Interpro

BRCT

FAT

FATC

OB-fold

OMIM

ataxia-telangiectasia

Bloom syndrome

Werner syndrome

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Glossary

Hypomorphic mutation

A mutation that reduces, but does not completely eliminate, the function of a gene.

Seckel syndrome

A rare autosomal-recessive disorder that is characterized by microcephaly, mental retardation and growth retardation. One form is caused by mutations in the ataxia-telangiectasia mutated and RAD3-related (ATR) gene.

Replication stress

A problem during DNA replication that is caused by DNA lesions, inadequate deoxynucleotide supplies or other difficulties that interfere with replication-fork movement.

Replication protein A

(RPA). A heterotrimeric single-stranded DNA-binding protein complex with multiple activities in nucleic acid metabolism.

Clamp loader

A protein complex that binds and then assembles a protein clamp onto the DNA at a 3′ hydroxyl primer end for DNA replication or a 5′ phosphate primer end for checkpoint signalling.

End resection

The nuclease-dependent removal of base pairs at a double-strand break to leave an extended single-stranded DNA end with a recessed 5′ end.

Nucleotide-excision repair

A process in which a small region of the DNA strand that surrounds a bulky DNA lesion is removed from the DNA helix as an oligonucleotide.

BRCT domain

An evolutionarily conserved phospho-Ser/Thr-interaction motif that was identified first in the C-terminal part of breast cancer-1 (BRCA1) and subsequently in several other checkpoint mediators.

MRN complex

A double-strand-break-sensing complex that contains meiotic recombination protein-11 (MRE11), RAD50 and Nijmegen breakage syndrome protein-1 (NBS1) and that is important in the recruitment and activation of ataxia-telangiectasia mutated (ATM) kinase.

Cellular senescence

A nearly irreversible stage of permanent G1 cell-cycle arrest that is linked to morphological changes (for example, flattening of the cells), metabolic changes and changes in gene expression.

HEAT repeat

A tandemly repeated, 37–47-amino-acid module that forms an extended α-helical structure. It is named after four proteins: huntingtin, elongation factor-3 (EF3), protein phosphatase-2A (PP2A) and target of rapamycin-1 (TOR1).

Replisome

A multiprotein complex at the junction of the DNA replication fork that contains all of the enzymes that are required for DNA replication.

Nonsense-mediated mRNA decay

A pathway that eliminates mRNAs that bear premature stop codons.

Exon-junction complex

A complex of proteins that is deposited, as a consequence of pre-mRNA splicing, 20–24 nucleotides upstream of the splicing-generated exon–exon junctions of newly synthesized mRNA.

MCM2–7 complex

A complex of 6 minichromosome maintenance proteins (MCM2–7) that functions, together with accessory proteins, as the replicative helicase that unwinds double-stranded DNA.

Polo-like kinase

An evolutionarily conserved Ser/Thr kinase with functions in mitosis and checkpoint signalling.

Collapsed replication fork

A blocked replication fork that has lost components of the replisome.

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Cimprich, K., Cortez, D. ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9, 616–627 (2008). https://doi.org/10.1038/nrm2450

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