Jie Du, Fuqiang Chen, Chenghong Du, Wenna Zhao, Zihan Chen, Zhenhua Ding, Meijuan Zhou
{"title":"Amodiaquine ameliorates stress-induced premature cellular senescence via promoting SIRT1-mediated HR repair.","authors":"Jie Du, Fuqiang Chen, Chenghong Du, Wenna Zhao, Zihan Chen, Zhenhua Ding, Meijuan Zhou","doi":"10.1038/s41420-024-02201-1","DOIUrl":null,"url":null,"abstract":"<p><p>DNA damage is considered to be a potentially unifying driver of ageing, and the stalling of DNA damage repair accelerates the cellular senescence. However, augmenting DNA repair has remained a great challenge due to the intricate repair mechanisms specific for multiple types of lesions. Herein, we miniaturized our modified detecting system for homologous recombination (HR) into a 96-well-based platform and performed a high-throughput chemical screen for FDA-approved drugs. We uncovered that amodiaquine could significantly augment HR repair at the noncytotoxic concentration. Further experiments demonstrated that amodiaquine remarkably suppressed stress-induced premature cellular senescence (SIPS), as evidenced by senescence-associated beta-galactosidase (SA-β-gal) staining or senescence-related markers p21<sup>WAF1</sup> and p16<sup>ink4a</sup>, and the expression of several cytokines. Mechanistic studies revealed that the stimulation of HR repair by amodiaquine might be mostly attributable to the promotion of SIRT1 at the transcriptional level. Additionally, SIRT1 depletion abolished the amodiaquine-mediated effects on DNA repair and cellular senescence, indicating that amodiaquine delayed the onset of SIPS via a SIRT1-dependent pathway. Taken together, this experimental approach paved the way for the identification of compounds that augment HR activity, which could help to underscore the therapeutic potential of targeting DNA repair for treating aging-related diseases.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"10 1","pages":"434"},"PeriodicalIF":6.1000,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470136/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Death Discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41420-024-02201-1","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
DNA damage is considered to be a potentially unifying driver of ageing, and the stalling of DNA damage repair accelerates the cellular senescence. However, augmenting DNA repair has remained a great challenge due to the intricate repair mechanisms specific for multiple types of lesions. Herein, we miniaturized our modified detecting system for homologous recombination (HR) into a 96-well-based platform and performed a high-throughput chemical screen for FDA-approved drugs. We uncovered that amodiaquine could significantly augment HR repair at the noncytotoxic concentration. Further experiments demonstrated that amodiaquine remarkably suppressed stress-induced premature cellular senescence (SIPS), as evidenced by senescence-associated beta-galactosidase (SA-β-gal) staining or senescence-related markers p21WAF1 and p16ink4a, and the expression of several cytokines. Mechanistic studies revealed that the stimulation of HR repair by amodiaquine might be mostly attributable to the promotion of SIRT1 at the transcriptional level. Additionally, SIRT1 depletion abolished the amodiaquine-mediated effects on DNA repair and cellular senescence, indicating that amodiaquine delayed the onset of SIPS via a SIRT1-dependent pathway. Taken together, this experimental approach paved the way for the identification of compounds that augment HR activity, which could help to underscore the therapeutic potential of targeting DNA repair for treating aging-related diseases.
DNA 损伤被认为是老化的潜在统一驱动力，DNA 损伤修复的停滞会加速细胞衰老。然而，由于多种类型病变的修复机制错综复杂，加强DNA修复仍是一个巨大的挑战。在此，我们将改良的同源重组（HR）检测系统微型化到基于96孔的平台中，并对FDA批准的药物进行了高通量化学筛选。我们发现，在无细胞毒性浓度下，阿莫地喹能显著增强同源重组修复。进一步的实验表明，阿莫地喹能显著抑制应激诱导的细胞过早衰老（SIPS），衰老相关的β-半乳糖苷酶（SA-β-gal）染色或衰老相关标记物p21WAF1和p16ink4a以及多种细胞因子的表达都证明了这一点。机理研究显示，阿莫地喹对HR修复的刺激可能主要归因于SIRT1在转录水平上的促进作用。此外，SIRT1 的缺失会消除阿莫地喹介导的对 DNA 修复和细胞衰老的影响，这表明阿莫地喹通过 SIRT1 依赖性途径延缓了 SIPS 的发生。总之，这种实验方法为鉴定能增强HR活性的化合物铺平了道路，有助于强调针对DNA修复治疗衰老相关疾病的治疗潜力。
期刊介绍：
Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary.
Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
