衰老
Cockayne综合征
DNA损伤
生物
细胞生物学
下调和上调
组蛋白
DNA修复
组蛋白H3
转录因子
表型
遗传学
DNA
基因
核苷酸切除修复
作者
Clément Crochemore,Cristina Fernández-Molina,Benjamin Montagne,Audrey Salles,Miria Ricchetti
标识
DOI:10.1038/s41467-019-13314-y
摘要
Abstract Cellular senescence has causative links with ageing and age-related diseases, however, it remains unclear if progeroid factors cause senescence in normal cells. Here, we show that depletion of CSB, a protein mutated in progeroid Cockayne syndrome (CS), is the earliest known trigger of p21-dependent replicative senescence. CSB depletion promotes overexpression of the HTRA3 protease resulting in mitochondrial impairments, which are causally linked to CS pathological phenotypes. The CSB promoter is downregulated by histone H3 hypoacetylation during DNA damage-response. Mechanistically, CSB binds to the p21 promoter thereby downregulating its transcription and blocking replicative senescence in a p53-independent manner. This activity of CSB is independent of its role in the repair of UV-induced DNA damage. HTRA3 accumulation and senescence are partially rescued upon reduction of oxidative/nitrosative stress. These findings establish a CSB/p21 axis that acts as a barrier to replicative senescence, and link a progeroid factor with the process of regular ageing in human.
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