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.
Highlights
Cellular senescence has causative links with ageing and age-related diseases, it remains unclear if progeroid factors cause senescence in normal cells
To assess whether HTRA3, which is considered a prevalently mitochondrial protease[26], was expressed during cellular senescence, we examined population doubling of three independent IMR-90 serially passaged human embryonic fibroblasts (Fig. 1a)
Super-resolution structured illumination microscopy (SIM) of early-passage and senescent fibroblasts revealed that HTRA3 is not prevalently mitochondrial, and this condition does not appear to change upon senescence (Fig. 1d)
Summary
Cellular senescence has causative links with ageing and age-related diseases, it remains unclear if progeroid factors cause senescence in normal cells. 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. Senescence triggered by replication-induced DNA damage, or telomere shortening that determine a persistent DDR, and resulting in the stabilization of the transcription factor p53 and expression of the cyclin-dependent kinase inhibitor p21 (coded by p21Waf1)[9,10], is called replicative senescence. Stimuli such as genomic and epigenomic damage, oxidative and proteotoxic stress, and mitogenic signals that engage either the DDRdependent (p53/p21Waf1) pathway or activation of the CDKN2 locus through expression of the tumor suppressor p16 (encoded by p16Ink4) induce senescence[11]. Specific elimination of p16Ink4-positive cells in a progeroid mouse model delays the onset, or limits the progression, of aged-related symptoms[17]
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