An extending ATR–CHK1 circuitry: the replication stress response and beyond

doi:10.1016/j.gde.2021.07.003

Current Opinion in Genetics & Development

Volume 71, December 2021, Pages 92-98

https://doi.org/10.1016/j.gde.2021.07.003 Get rights and content

The maintenance of genomic integrity relies on the coordination of a wide range of cellular processes and efficient repair of DNA damage. Since its discovery over two decades ago, the ATR kinase has been recognized as the master regulator of the circuitry orchestrating the cellular responses to DNA damage and replication stress. Recent studies reveal that ATR additionally functions in the unperturbed cell cycle through its control of replication fork speed and stability, replication origin firing, completion of genome duplication, and chromosome segregation. Here, we discuss several recently discovered mechanisms through which ATR safeguards genomic integrity during the cell cycle, from S phase to mitosis.

Section snippets

ATR and replication origin firing

During S phase, DNA replication is initiated from ‘licensed’ origins [17]. Licensing occurs during G1 and involves the loading of MCM helicase hexamers onto DNA through the action of CDT1 and CDC6. Origin firing is triggered upon entry into S phase by the concerted action of CDK and CDC7 kinases, which promotes the assembly of the replisome at origins. Many more origins are licensed than required for a round of DNA replication, but most are passively replicated during S phase by replication

ATR functions at replication forks

Replication forks under stress trigger the recruitment of TOPBP1 through its interaction with the 9–1–1 clamp bound to ssDNA–dsDNA junctions. This recruitment puts TOPBP1 in close proximity to RPA-bound ATR–ATRIP, allowing TOPBP1 to stimulate ATR and enabling the phosphorylation of CHK1 [24,25]. Recent evidence suggests that TOPBP1 has an ability to form micrometer-sized nuclear condensates upon replication stress in order to amplify ATR activity [26^•]. This self-assembly of TOPBP1 requires

Functions of the ETAA1-ATR axis beyond S phase

When cells are exposed to DNA damage, ATR slows down replication in S phase and prevents the transition from G2 to M phase until DNA damage is resolved. Recent studies suggest that ATR also regulates the transition from S to G2, as well as mitosis, during the unperturbed cell cycle. Notably, these functions of ATR are linked to its activation by ETAA1 (Figure 2). The function of ETAA1 in ATR activation requires its direct interaction with ssDNA-bound RPA [8,9,43,44]. Moreover, ETAA1’s

Concluding remarks

While much attention is directed at the direct roles of the ATR–CHK1 pathway on genomic integrity, the transcriptional impacts of this pathway on cancer therapy are just beginning to unfold. For example, pulsed treatment of BRCA2-deficient cells to cisplatin induces the expression of PrimPol in an ATR-dependent mechanism [49]. This regime promotes cell fitness to future exposures to cisplatin by bypassing lesions through a repriming process. Cancer cells subject to intrinsic replication stress

Funding

No funding was received for this work.

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

A.S. is the recipient of postdoctoral fellowships from the Canadian Institutes of Health Research and Fonds de Recherche du Québec – Santé. L.Z. is the James and Patricia Poitras Endowed Chair in Cancer Research.

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View full text

An extending ATR–CHK1 circuitry: the replication stress response and beyond

Section snippets

ATR and replication origin firing

ATR functions at replication forks

Functions of the ETAA1-ATR axis beyond S phase

Concluding remarks

Funding

Conflict of interest statement

References and recommended reading

Acknowledgements

Mol Cell

Cell

J Biol Chem

J Cell Biol

Nat Commun

J Biol Chem

PNAS

Genes Dev

Mol Cell

Cancer Res

Cell Rep

Mol Cell

Genes Dev

Mol Cell

Cancer Res

Nucleic Acids Res

J Biol Chem

Science

Cell Rep

Nucleic Acids Res

The essential kinase ATR: ensuring faithful duplication of a challenging genome

Nat Rev Mol Cell Biol

DNA damage sensing by the ATM and ATR kinases

Cold Spring Harb Perspect Biol

ATR and ATRIP: partners in checkpoint signaling

Science

Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes

Science

Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint

Genes Dev

Activation of the ATR kinase by the RPA-binding protein ETAA1

Nat Cell Biol