Physiological concentrations of glucocorticoids induce pathological DNA double-strand breaks
Physiological concentrations of glucocorticoids induce pathological DNA double-strand breaks
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DOI：
10.1111/gtc.12993
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发表时间：
2022-12-07
期刊：
影响因子：
2.1
通讯作者：
Takeda，Shunichi
中科院分区：
文献类型：
--
作者：
Akter，Salma;Shimba，Akihiro;Takeda，Shunichi
类固醇激素通过激活核受体来诱导靶基因的转录。对包括激素在内的各种刺激的早期转录反应涉及到转录调控序列中拓扑异构酶II(TOP2)的活性催化。TOP2通过瞬时产生双链断裂(DSB)来解开DNA，其中TOP2共价结合到DSB末端。当TOP2不能重新连接时，被称为“流产”催化，产生的DSB被酪氨酰DNA磷酸二酯酶2(TDP2)和非同源末端连接(NHEJ)修复。类固醇皮质醇是最重要的糖皮质激素，地塞米松(Dex)是一种人工合成的糖皮质激素，在临床上被广泛用于抑制炎症。我们在此揭示了临床相关浓度的地塞米松和生理浓度的皮质醇有效地在缺乏TDP2和NHEJ的G1期细胞中诱导DSB。DSB的诱导依赖于糖皮质激素受体(GR)和TOP2。考虑到TDP2在从DSB末端去除TOP2加合物的特定作用，诱导的DSB很可能是停滞的TOP2-DSB复合体。抑制RNA聚合酶II对G1期DSB的形成仅有轻微的抑制作用。我们认为皮质醇和地塞米松经常通过TOP2在转录调控序列(包括启动子或增强子)上的流产催化产生DSB，其中活跃的TOP2催化发生在早期的转录反应中。
Steroid hormones induce the transcription of target genes by activating nuclear receptors. Early transcriptional response to various stimuli, including hormones, involves the active catalysis of topoisomerase II (TOP2) at transcription regulatory sequences. TOP2 untangles DNAs by transiently generating double‐strand breaks (DSBs), where TOP2 covalently binds to DSB ends. When TOP2 fails to rejoin, called “abortive” catalysis, the resulting DSBs are repaired by tyrosyl‐DNA phosphodiesterase 2 (TDP2) and non‐homologous end‐joining (NHEJ). A steroid, cortisol, is the most important glucocorticoid, and dexamethasone (Dex), a synthetic glucocorticoid, is widely used for suppressing inflammation in clinics. We here revealed that clinically relevant concentrations of Dex and physiological concentrations of cortisol efficiently induce DSBs in G1phase cells deficient in TDP2 and NHEJ. The DSB induction depends on glucocorticoid receptor (GR) and TOP2. Considering the specific role of TDP2 in removing TOP2 adducts from DSB ends, induced DSBs most likely represent stalled TOP2‐DSB complexes. Inhibition of RNA polymerase II suppressed the DSBs formation only modestly in the G1phase. We propose that cortisol and Dex frequently generate DSBs through the abortive catalysis of TOP2 at transcriptional regulatory sequences, including promoters or enhancers, where active TOP2 catalysis occurs during early transcriptional response.