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<p>Targeted inhibition of DNA damage response proteins has received significant clinical attention owing to the success of PARP inhibitors. Due to G1/S checkpoint inactivation, cancer cells are reliant on the G2/M checkpoint to cope with elevated DNA replication stress. We demonstrated that a single induction of 8-oxo-guanine at telomeres in cancer cells was sufficient to induce replication stress but was not cytotoxic. Here, we find inhibition of ATR, CHK1, or WEE1 after induction of telomeric 8-oxo-guanine significantly reduced cell viability by inducing genome instability. This occurred at doses markedly less than those required to increase instability in non-cancerous cells. We determined the mechanism of this instability is due to insufficient levels of RPA for damaged telomeres, forcing cells to progress through S-phase with telomere damage and exit G2-phase prematurely, prolonging mitosis. This study demonstrates targeted oxidative base damage at telomeres can enhance the therapeutic efficacy of ATR inhibition in cancer.</p><p></p>

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Oxidative base damage to telomeres sensitizes cancer cells to ATR inhibition

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月11日

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  • Alex Garbouchian,
  • Natalia Cestari Moreno,
  • Aninda Dey,
  • Christopher J. Bakkenist,
  • Patricia L. Opresko,
  • Ryan P. Barnes

摘要

Targeted inhibition of DNA damage response proteins has received significant clinical attention owing to the success of PARP inhibitors. Due to G1/S checkpoint inactivation, cancer cells are reliant on the G2/M checkpoint to cope with elevated DNA replication stress. We demonstrated that a single induction of 8-oxo-guanine at telomeres in cancer cells was sufficient to induce replication stress but was not cytotoxic. Here, we find inhibition of ATR, CHK1, or WEE1 after induction of telomeric 8-oxo-guanine significantly reduced cell viability by inducing genome instability. This occurred at doses markedly less than those required to increase instability in non-cancerous cells. We determined the mechanism of this instability is due to insufficient levels of RPA for damaged telomeres, forcing cells to progress through S-phase with telomere damage and exit G2-phase prematurely, prolonging mitosis. This study demonstrates targeted oxidative base damage at telomeres can enhance the therapeutic efficacy of ATR inhibition in cancer.