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Functions, Regulation, and Therapeutic Implications of the ATR Checkpoint Pathway
Stephanie A Yazinski1, Lee Zou1,2
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129;
Abstract:
The ATR (ATM and rad3-related) pathway is crucial for proliferation, responding to DNA replication stress and DNA damage. This critical signaling pathway is carefully orchestrated through a multistep process requiring initial priming of ATR prior to damage, recruitment of ATR to DNA damage lesions, activation of ATR signaling, and, finally, modulation of ATR activity through a variety of post-translational modifications. Following activation, ATR functions in several vital cellular processes, including suppression of replication origin firing, promotion of deoxynucleotide synthesis and replication fork restart, prevention of double-stranded DNA break formation, and avoidance of replication catastrophe and mitotic catastrophe. In many cancers, tumor cells have increased dependence on ATR signaling for survival, making ATR a promising target for cancer therapy. Tumor cells compromised in DNA repair pathways or DNA damage checkpoints, cells reliant on homologous recombination, and cells with increased replication stress are particularly sensitive to ATR inhibition. Understanding ATR signaling and modulation is essential to unraveling which tumors have increased dependence on ATR signaling as well as how the ATR pathway can best be exploited for targeted cancer therapy.
Insights
The ATM and rad3-related (ATR) pathway is vital for cell proliferation and DNA damage response. Inhibiting ATR shows promise for cancer therapy, especially in tumors reliant on this pathway for survival.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Biology
Background:
- The ATM and rad3-related (ATR) pathway is essential for cellular response to DNA replication stress and DNA damage.
- ATR signaling involves a complex multistep process including priming, recruitment, activation, and modulation via post-translational modifications.
Purpose of the Study:
- To elucidate the critical roles of ATR signaling in cellular processes.
- To identify cancer types and conditions where ATR inhibition could be a viable therapeutic strategy.
Main Methods:
- Review of existing literature on ATR pathway signaling and its role in DNA damage response.
- Analysis of ATR pathway's function in cancer cell survival and proliferation.
- Identification of cancer cell vulnerabilities to ATR inhibition.
Main Results:
- Activated ATR regulates key cellular processes such as origin firing suppression, deoxynucleotide synthesis, and replication fork restart.
- ATR pathway plays a crucial role in preventing DNA breaks and catastrophic cellular events.
- Tumor cells with compromised DNA repair, checkpoint deficiencies, or increased replication stress exhibit heightened dependence on ATR signaling.
Conclusions:
- ATR is a critical regulator of DNA replication and damage response, essential for cancer cell survival.
- Targeting the ATR pathway offers a promising therapeutic strategy for specific cancer types, particularly those with inherent DNA repair defects or high replication stress.
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