Exosome component 1 cleaves single-stranded DNA and sensitizes human kidney renal clear cell carcinoma cells to poly(ADP-ribose) polymerase inhibitor.
Exosome component 1 cleaves single-stranded DNA and sensitizes human kidney renal clear cell carcinoma cells to poly(ADP-ribose) polymerase inhibitor.
复制标题
外泌体组分1切割单链DNA并使人肾透明细胞癌细胞对聚（ADP-核糖）聚合酶抑制剂敏感。
作者：
Liu Q;Xiao Q;Sun Z;Wang B;Wang L;Wang N;Wang K;Song C;Yang Q
靶向DNA修复途径为人类癌症提供了重要的治疗策略。然而，DNA修复抑制剂未能使患者明显受益，因此需要开发新的策略。在这里，我们发现外泌体组分1（EXOSC 1）促进DNA损伤，并使人肾透明细胞癌（KIRC）细胞对DNA修复抑制剂敏感。考虑到内源性突变源（ESM）不断攻击基因组DNA，并可能使人类癌细胞对抑制剂敏感，我们首先分析了单个基因表达与KIRC突变之间的统计关系。在候选者中，EXOSC 1通过优先切割单链DNA中的C位点而最显著地促进DNA损伤和随后的突变。一致地，EXOSC 1与人KIRC中编码链中的C>A颠换比与模板链中的C>A颠换更显著相关。值得注意的是，具有高EXOSC 1的KIRC患者显示出不良预后，并且EXOSC 1使人癌细胞对聚（ADP-核糖）聚合酶抑制剂敏感。这些结果表明，EXOSC 1在KIRC中起着ESM的作用，靶向EXOSC 1可能是一种潜在的治疗策略。
Targeting DNA repair pathway offers an important therapeutic strategy for Homo sapiens (human) cancers. However, the failure of DNA repair inhibitors to markedly benefit patients necessitates the development of new strategies. Here, we show that exosome component 1 (EXOSC1) promotes DNA damages and sensitizes human kidney renal clear cell carcinoma (KIRC) cells to DNA repair inhibitor. Considering that endogenous source of mutation (ESM) constantly assaults genomic DNA and likely sensitizes human cancer cells to the inhibitor, we first analyzed the statistical relationship between the expression of individual genes and the mutations for KIRC. Among the candidates, EXOSC1 most notably promoted DNA damages and subsequent mutations via preferentially cleaving C site(s) in single-stranded DNA. Consistently, EXOSC1 was more significantly correlated with C>A transversions in coding strands than these in template strands in human KIRC. Notably, KIRC patients with high EXOSC1 showed a poor prognosis, and EXOSC1 sensitized human cancer cells to poly(ADP-ribose) polymerase inhibitors. These results show that EXOSC1 acts as an ESM in KIRC, and targeting EXOSC1 might be a potential therapeutic strategy.