Suman Panda, Tanaya Roychowdhury, Anindya Dutta, Sourio Chakraborty, Tanya Das and Subhrangsu Chatterjee*,
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引用次数: 0
Abstract
Most of the human cancers are dependent on telomerase to extend the telomeres. But ∼10% of all cancers use a telomerase-independent, homologous recombination mediated pathway called alternative lengthening of telomeres (ALT). Due to the poor prognosis, ALT status is not being considered yet in the diagnosis of cancer. No such specific treatment is available to date for ALT positive cancers. ALT positive cancers are dependent on replication stress to deploy DNA repair pathways to the telomeres to execute homologous recombination mediated telomere extension. SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like 1) is associated with the ALT telomeres to resolve replication stress thus providing telomere stability. Thus, the dependency on replication stress regulatory factors like SMARCAL1 made it a suitable therapeutic target for the treatment of ALT positive cancers. In this study, we found a significant downregulation of SMARCAL1 expression by stabilizing the G-quadruplex (G4) motif found in the promoter of SMARCAL1 by potent G4 stabilizers, like TMPyP4 and BRACO-19. SMARCAL1 downregulation led toward the increased localization of PML (promyelocytic leukemia) bodies in ALT telomeres and triggered the formation of APBs (ALT-associated promyelocytic leukemia bodies) in ALT positive cell lines, increasing telomere replication stress and DNA damage at a genomic level. Induction of replication stress and hyper-recombinogenic phenotype in ALT positive cells mediated by G4 stabilizing molecules already highlighted their possible application as a new therapeutic window to target ALT positive tumors. In accordance with this, our study will also provide a valuable insight toward the development of G4-based ALT therapeutics targeting SMARCAL1.
大多数人类癌症都依赖端粒酶来延长端粒。但有10%的癌症使用一种不依赖端粒酶的同源重组介导的途径,即端粒替代性延长(ALT)。由于预后不佳,目前在诊断癌症时还没有考虑 ALT 状态。迄今为止,还没有针对 ALT 阳性癌症的特殊治疗方法。ALT阳性癌症依赖复制压力将DNA修复途径部署到端粒,以执行同源重组介导的端粒延长。SMARCAL1(与SWI/SNF相关的、基质相关的、依赖肌动蛋白的染色质调节器,类A亚家族1)与ALT端粒相关,可解决复制压力,从而提供端粒稳定性。因此,SMARCAL1等复制压力调节因子的依赖性使其成为治疗ALT阳性癌症的合适治疗靶点。在这项研究中,我们发现通过强效G4稳定剂(如TMPyP4和BRACO-19)稳定SMARCAL1启动子中的G-四叠体(G4)图案,可以显著下调SMARCAL1的表达。SMARCAL1 下调导致 PML(早幼粒细胞白血病)体在 ALT 端粒中的定位增加,并在 ALT 阳性细胞系中引发 APB(ALT 相关早幼粒细胞白血病体)的形成,从而在基因组水平上增加端粒复制压力和 DNA 损伤。由 G4 稳定分子介导的 ALT 阳性细胞复制压力和超重组表型的诱导已经突出表明,它们可能成为针对 ALT 阳性肿瘤的新的治疗窗口。因此,我们的研究也将为开发基于 G4 的、以 SMARCAL1 为靶点的 ALT 治疗药物提供有价值的见解。
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.