6-Thioguanine incorporates into RNA and induces adenosine-to-inosine editing in acute lymphoblastic leukemia cells

摘要

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(^(S)G)nucleotide that can be incorporated into the genome during DNA replication.^(S)G in genomic DNA could induce cell death by triggering the post-replicative mismatch repair(MMR)pathway.Meanwhile,incorporation of 6TG into the Cp G sites could perturb the global DNA methylation and gene regulation.However,the effect of 6TG on RNA modifications is still unknown.Adenosine-toinosine(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 ^(S)G could be incorporated into various RNA species,with m RNA having the most abundant ^(S)G.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.