Inhibition of nucleolar transcription by oxaliplatin involves ATM/ATR kinase signaling.
Inhibition of nucleolar transcription by oxaliplatin involves ATM/ATR kinase signaling.
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DOI：
10.1016/j.chembiol.2023.06.010
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发表时间：
2023-06
影响因子：
8.6
通讯作者：
Misha Nechay;Danyang Wang;Ralph E. Kleiner
中科院分区：
文献类型：
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作者：
Misha Nechay;Danyang Wang;Ralph E. Kleiner
铂（Pt）化合物是一类重要的抗癌治疗剂，但关于其作用机制仍存在突出问题。在这里，我们证明了奥沙利铂，一种用于治疗结直肠癌的铂类药物，通过ATM和ATR信号抑制rRNA转录，并诱导DNA损伤和核仁破坏。我们发现，奥沙利铂导致核仁DNA损伤反应蛋白（n-DDR）NBS 1和TOPBP 1的核仁积累;然而，转录抑制不依赖于NBS 1或TOPBP 1，奥沙利铂也不诱导大量的核仁DNA损伤，将核仁反应与先前表征的n-DDR途径区分开来。综上所述，我们的工作表明，奥沙利铂诱导了一种独特的ATM和ATR信号通路，在不存在直接核仁DNA损伤的情况下抑制Pol I转录，证明了核仁应激和转录沉默如何与DNA损伤信号通路相关，并突出了Pt药物细胞毒性的重要机制。
Platinum (Pt) compounds are an important class of anti-cancer therapeutics, but outstanding questions remain regarding their mechanism of action. Here, we demonstrate that oxaliplatin, a Pt drug used to treat colorectal cancer, inhibits rRNA transcription through ATM and ATR signaling, and induces DNA damage and nucleolar disruption. We show that oxaliplatin causes nucleolar accumulation of the nucleolar DNA damage response proteins (n-DDR) NBS1 and TOPBP1; however transcriptional inhibition does not depend upon NBS1 or TOPBP1, nor does oxaliplatin induce substantial amounts of nucleolar DNA damage, distinguishing the nucleolar response from previously characterized n-DDR pathways. Taken together, our work indicates that oxaliplatin induces a distinct ATM and ATR signaling pathway that functions to inhibit Pol I transcription in the absence of direct nucleolar DNA damage, demonstrating how nucleolar stress and transcriptional silencing can be linked to DNA damage signaling and highlighting an important mechanism of Pt drug cytotoxicity.