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由驱动的转录应激触发了厌食性DNA损伤反应
Lee Mulderrig1,2, Juan I Garaycoechea3, Zewen K Tuong4,5
1MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Nature
|November 25, 2021
概括
内生甲会导致DNA损伤,阻碍转录并导致可凯恩综合征的症状. 阻断GDF15信号可以缓解缓解,这表明它在疾病发病过程中起作用.
科学领域:
- 分子生物学
- 遗传学
- 毒理学
背景情况:
- 内部的DNA损伤会破坏细胞的转录过程.
- 由于CSA或CSB蛋白的突变, 卡凯恩综合征是一种人类疾病, 缺乏这种DNA损伤反应.
- 内生DNA损伤的来源及其与Cockayne综合征退行性特征的联系尚不清楚.
研究的目的:
- 为了确定内源性DNA损伤的来源.
- 调查这种损伤的生理后果.
- 了解CSB蛋白在防止甲引起的DNA损伤和相关症状中的作用.
主要方法:
- 使用的小鼠模型缺乏甲清除 (Adh5-/-) 和CSB (Csb(m/m)).
- 使用单细胞RNA测序来分析基因表达变化.
- 进行抗GDF15抗体治疗以评估治疗效果.
主要成果:
- 缺少甲清除和CSB的小鼠表现出缓解症,神经退行症和功能衰竭,模仿了考凯恩综合征.
- 甲诱导的转录应激增加了附近细胞中的厌食性GDF15.
- 对GDF15抗体的治疗改善了研究小鼠的缓解性.
结论:
- 在和大脑中,CSB蛋白可以防止内源甲对DNA造成的损伤.
- GDF15的上调有助于可凯恩综合征的缓解症和潜在的化疗诱导的体重减轻.
- 这种细胞反应可能是为了促进对食物中的基因毒素的厌恶.
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