深圳大学医学院朱卫国小组取得一项新突破。他们揭示了组蛋白H1脱酰胺促进染色质松弛DNA修复。相关论文于2025年4月16日发表于国际顶尖学术期刊《自然》杂志上。

在这里，课题组研究人员发现CTP合成酶1 （CTPS1）催化H1天冬酰胺残基76和77的脱酰胺引发DNA损伤后赖氨酸75的连续乙酰化，并且这种H1的双重修饰与染色质打开有关。从机制上讲，组蛋白乙酰转移酶p300表现出对脱酰胺H1作为底物的偏好，这表明H1脱酰胺是随后乙酰化的先决条件。

此外，在同种异种移植模型和临床队列中，CTPS1的高表达与癌症放疗的耐药有关。这些发现为连接蛋白如何调节DNA损伤反应中的动态染色质改变提供了新的见解。

研究人员表示，在DNA双链断裂周围形成可接近的染色质对其有效修复至关重要。虽然已知连接体组蛋白H1促进高阶染色质紧致，但H1修饰在DNA损伤反应中调节染色质松弛的机制尚不清楚。

附：英文原文

Title: Histone H1 deamidation facilitates chromatin relaxation for DNA repair

Author: Tian, Yuan, Feng, Tingting, Zhang, Jun, Meng, Qingren, Zhan, Wenxin, Tang, Ming, Liu, Chaohua, Li, Mengyan, Tao, Wenhui, Shu, Yuxin, Zhang, Yu, Chen, Feng, Takeda, Shunichi, Zhu, Qian, Lu, Xiaopeng, Zhu, Wei-Guo

Issue&Volume: 2025-04-16

Abstract: The formation of accessible chromatin around DNA double-strand breaks is essential for their efficient repair1. Although the linker histone H1 is known to facilitate higher-order chromatin compaction2,3, the mechanisms by which H1 modifications regulate chromatin relaxation in response to DNA damage are unclear. Here we show that CTP synthase 1 (CTPS1)-catalysed deamidation of H1 asparagine residues 76 and 77 triggers the sequential acetylation of lysine 75 following DNA damage, and this dual modification of H1 is associated with chromatin opening. Mechanistically, the histone acetyltransferase p300 showed a preference for deamidated H1 as a substrate, establishing H1 deamidation as a prerequisite for subsequent acetylation. Moreover, high expression of CTPS1 was associated with resistance to cancer radiotherapy, in both mouse xenograft models and clinical cohorts. These findings provide new insights into how linker histones regulate dynamic chromatin alterations in the DNA damage response.

DOI: 10.1038/s41586-025-08835-0

Source: https://www.nature.com/articles/s41586-025-08835-0