Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore.
Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore.
Curr Opin Pharmacol. 2024 Jun;76:102460. doi: 10.1016/j.coph.2024.102460. Epub 2024 May 21.
Shelterin proteins regulate genomic stability by preventing inappropriate DNA damage responses (DDRs) at telomeres. Unprotected telomeres lead to persistent DDR causing cell cycle inhibition, growth arrest, and apoptosis. Cancer cells rely on DDR to protect themselves from DNA lesions and exogenous DNA-damaging agents such as chemotherapy and radiotherapy. Therefore, targeting DDR machinery is a promising strategy to increase the sensitivity of cancer cells to existing cancer therapies. However, the success of these DDR inhibitors depends on other mutations, and over time, patients develop resistance to these therapies. This suggests the need for alternative approaches. One promising strategy is co-inhibiting shelterin proteins with DDR molecules, which would offset cellular fitness in DNA repair in a mutation-independent manner. This review highlights the associations and dependencies of the shelterin complex with the DDR proteins and discusses potential co-inhibition strategies that might improve the therapeutic potential of current inhibitors.
庇护蛋白通过防止端粒处不合适的 DNA 损伤反应（DDR）来调节基因组稳定性。未受保护的端粒会导致持续的 DDR，从而导致细胞周期抑制、生长停滞和细胞凋亡。癌细胞依赖 DDR 来保护自己免受 DNA 损伤和外源性 DNA 损伤剂（如化疗和放疗）的侵害。因此，靶向 DDR 机制是提高癌细胞对现有癌症疗法敏感性的一种有前途的策略。然而，这些 DDR 抑制剂的成功取决于其他突变，并且随着时间的推移，患者会对这些疗法产生耐药性。这表明需要替代方法。一种很有前途的策略是与 DDR 分子共同抑制庇护蛋白，这将以一种不依赖于突变的方式抵消细胞在 DNA 修复方面的适应性。这篇综述强调了庇护复合物与 DDR 蛋白的关联和依赖性，并讨论了可能改善当前抑制剂治疗潜力的潜在共同抑制策略。
