{"title":"Shaping DNA damage responses: Therapeutic potential of targeting telomeric proteins and DNA repair factors in cancer","authors":"Yu Bin Ng, Semih Can Akincilar","doi":"10.1016/j.coph.2024.102460","DOIUrl":null,"url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":50603,"journal":{"name":"Current Opinion in Pharmacology","volume":"76 ","pages":"Article 102460"},"PeriodicalIF":4.0000,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Opinion in Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1471489224000304","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
Abstract
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.
Shelterin 蛋白通过防止端粒上不适当的 DNA 损伤反应(DDR)来调节基因组的稳定性。不受保护的端粒会导致持续的DDR,引起细胞周期抑制、生长停滞和细胞凋亡。癌细胞依赖 DDR 来保护自己免受 DNA 病变和化疗、放疗等外源性 DNA 损伤药物的伤害。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,随着时间的推移,患者会对这些疗法产生抗药性。这表明需要采用替代方法。一种很有前景的策略是将保护蛋白与 DDR 分子共同抑制,这将以一种与突变无关的方式抵消 DNA 修复中的细胞适应性。本综述强调了保护蛋白复合物与 DDR 蛋白的关联性和依赖性,并讨论了潜在的联合抑制策略,这些策略可能会提高当前抑制剂的治疗潜力。
期刊介绍:
Current Opinion in Pharmacology (COPHAR) publishes authoritative, comprehensive, and systematic reviews. COPHAR helps specialists keep up to date with a clear and readable synthesis on current advances in pharmacology and drug discovery. Expert authors annotate the most interesting papers from the expanding volume of information published today, saving valuable time and giving the reader insight on areas of importance.