大多数人类癌症都依赖端粒酶来延长端粒。但约 10% 的癌症使用不依赖端粒酶的同源重组介导途径，称为端粒替代延长 (ALT)。由于预后不良，在癌症诊断中尚未考虑 ALT 状态。迄今为止，还没有针对 ALT 阳性癌症的特异性治疗方法。 ALT 阳性癌症依赖于复制应激将 DNA 修复途径部署到端粒，以执行同源重组介导的端粒延伸。 SMARCAL1（SWI/SNF 相关、基质相关、肌动蛋白依赖性染色质调节因子，A 亚家族 1）与 ALT 端粒相关，可解决复制应激，从而提供端粒稳定性。因此，对 SMARCAL1 等复制应激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，我们通过有效的 G4 稳定剂（如 TMPyP4 和 BRACO-19）稳定 SMARCAL1 启动子中的 G-四链体 (G4) 基序，发现 SMARCAL1 表达显着下调。 SMARCAL1 下调导致 ALT 端粒中 PML（早幼粒细胞白血病）小体的定位增加，并触发 ALT 阳性细胞系中 APB（ALT 相关早幼粒细胞白血病小体）的形成，增加基因组水平的端粒复制应激和 DNA 损伤。 G4 稳定分子介导的 ALT 阳性细胞中复制应激和超重组表型的诱导已经凸显了它们作为针对 ALT 阳性肿瘤的新治疗窗口的可能应用。据此，我们的研究还将为开发针对 SMARCAL1 的基于 G4 的 ALT 疗法提供宝贵的见解。

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.