6-Thioguanine (6TG) is a widely used chemotherapeutic agent for the treatment of a variety of human diseases including acute lymphoblastic leukemia. After entry into cells, 6TG is metabolically converted into 6-thioguanosine (^SG) nucleotide that can be incorporated into the genome during DNA replication. ^SG in genomic DNA could induce cell death by triggering the post-replicative mismatch repair (MMR) pathway. Meanwhile, incorporation of 6TG into the CpG sites could perturb the global DNA methylation and gene regulation. However, the effect of 6TG on RNA modifications is still unknown. Adenosine-to-inosine (A-to-I) editing in RNA is one of the most common post-transcriptional modifications in mammals and there is growing evidence showing the significant alteration of A-to-I RNA editing in tumor tissues compared to normal tissues. In the current study, we examined the incorporation of 6TG into RNA and investigated its effect on A-to-I editing of bladder cancer-associated protein (BLCAP) transcript in acute lymphoblastic leukemia cells. The results demonstrated that ^SG could be incorporated into various RNA species, with mRNA having the most abundant ^SG. In addition, the results showed 6TG treatment elevated A-to-I editing in BLCAP transcript through upregulating adenosine deaminase 2 acting on RNA (ADAR2), which eventually contributes to the decreased cell viability. This study highlights a new mechanism of the cytotoxicity of 6TG in inducing cell death.

6-硫鸟嘌呤 (6TG) 是一种广泛使用的化学治疗剂，用于治疗包括急性淋巴细胞白血病在内的多种人类疾病。进入细胞后，6TG 代谢转化为 6-硫鸟苷 (SG ⁾核苷酸，可在 DNA 复制过程中整合到基因组中。^小号基因组 DNA 中的 G 可以通过触发复制后错配修复 (MMR) 途径诱导细胞死亡。同时，将 6TG 掺入 CpG 位点可能会扰乱全球 DNA 甲基化和基因调控。然而，6TG 对 RNA 修饰的影响仍然未知。RNA 中的腺苷到肌苷 (A-to-I) 编辑是哺乳动物中最常见的转录后修饰之一，越来越多的证据表明，与正常组织相比，肿瘤组织中的 A-to-I RNA 编辑发生了显着变化组织。在目前的研究中，我们检查了 6TG 与 RNA 的结合，并研究了其对急性淋巴细胞白血病细胞中膀胱癌相关蛋白 (BLCAP) 转录物的 A-to-I 编辑的影响。结果表明，^SG 可以整合到各种 RNA 物种中，其中 mRNA 具有最丰富的^S G。此外，结果显示 6TG 处理通过上调作用于 RNA 的腺苷脱氨酶 2 (ADAR2) 提高了 BLCAP 转录物中的 A-to-I 编辑，最终导致细胞活力下降。该研究强调了6TG诱导细胞死亡的细胞毒性新机制。