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醛驱动的转录压力引发一种厌食性DNA损伤反应
2021-11-27 19:44
来源：小柯机器人

英国牛津大学Ketan J. Patel团队发现，醛驱动的转录压力引发一种厌食性DNA损伤反应。该研究于2021年11月24日在线发表于国际一流学术期刊《自然》。

据研究人员介绍，内源性DNA损伤可扰乱转录，引发多方面的细胞反应，修复损伤，降解RNA聚合酶II并关闭全局转录。这种反应在人类疾病科克因综合症中是不存在的，它是由科克因综合症A（CSA）或CSB蛋白的丢失引起的。然而，内源性DNA损伤的来源以及如何导致这种疾病的突出退行性特征仍然是未知的。
 
研究人员发现，内源性的甲醛阻碍了转录，具有明显的生理后果。缺少甲醛清除功能的小鼠（Adh5-/-）和CSB（Csbm/m；Csb也被称为Ercc6）会出现恶病质和神经变性，并容易肾脏衰竭，这些特征类似于人类的科克因综合症。利用单细胞RNA测序，研究人员发现甲醛驱动的转录压力刺激肾脏近端小管细胞的一个表达厌食肽GDF15的亚群。用GDF15抗体阻断这种反应可以减轻Adh5-/-Csbm/m小鼠的恶病质。因此，CSB为肾脏和大脑提供保护，防止内源性甲醛引起的DNA损伤，同时也抑制了一种厌食的内分泌信号。这种信号的激活可能有助于在科克因综合征中观察到的恶病质，以及化疗引起的厌食性体重下降。这种反应演化目的是确保对食物中基因毒素的厌恶。
 
附：英文原文

Title: Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response

Author: Mulderrig, Lee, Garaycoechea, Juan I., Tuong, Zewen K., Millington, Christopher L., Dingler, Felix A., Ferdinand, John R., Gaul, Liam, Tadross, John A., Arends, Mark J., ORahilly, Stephen, Crossan, Gerry P., Clatworthy, Menna R., Patel, Ketan J.

Issue&Volume: 2021-11-24

Abstract: Endogenous DNA damage can perturb transcription, triggering a multifaceted cellular response that repairs the damage, degrades RNA polymerase II and shuts down global transcription1,2,3,4. This response is absent in the human disease Cockayne syndrome, which is caused by loss of the Cockayne syndrome A (CSA) or CSB proteins5,6,7. However, the source of endogenous DNA damage and how this leads to the prominent degenerative features of this disease remain unknown. Here we find that endogenous formaldehyde impedes transcription, with marked physiological consequences. Mice deficient in formaldehyde clearance (Adh5/) and CSB (Csbm/m; Csb is also known as Ercc6) develop cachexia and neurodegeneration, and succumb to kidney failure, features that resemble human Cockayne syndrome. Using single-cell RNA sequencing, we find that formaldehyde-driven transcriptional stress stimulates the expression of the anorexiogenic peptide GDF15 by a subset of kidney proximal tubule cells. Blocking this response with an anti-GDF15 antibody alleviates cachexia in Adh5/Csbm/m mice. Therefore, CSB provides protection to the kidney and brain against DNA damage caused by endogenous formaldehyde, while also suppressing an anorexic endocrine signal. The activation of this signal might contribute to the cachexia observed in Cockayne syndrome as well as chemotherapy-induced anorectic weight loss. A plausible evolutionary purpose for such a response is to ensure aversion to genotoxins in food.

DOI: 10.1038/s41586-021-04133-7

Source: https://www.nature.com/articles/s41586-021-04133-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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