scholarly journals The H2A.J histone variant contributes to Interferon-Stimulated Gene expression in senescence by its weak interaction with H1 and the derepression of repeated DNA sequences

2020 ◽  
Author(s):  
Adele Mangelinck ◽  
Clement Coudereau ◽  
Regis Courbeyrette ◽  
Khalid Ouararhni ◽  
Ali Hamiche ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Sequences ◽  
Transcriptional Activity ◽  
Human Fibroblasts ◽  
Histone Variant ◽  
Repeated Dna ◽  
Inflammatory Gene Expression ◽  
Repeated Dna Sequences ◽  
Inflammatory Gene

The histone variant H2A.J was previously shown to accumulate in senescent human fibroblasts with persistent DNA damage to promote inflammatory gene expression, but its mechanism of action was unknown. We show that H2A.J accumulation contributes to weakening the association of histone H1 to chromatin and increasing its turnover. Decreased H1 in senescence is correlated with increased expression of some repeated DNA sequences, increased expression of STAT/IRF transcription factors, and transcriptional activation of Interferon-Stimulated Genes (ISGs). The H2A.J-specific Val-11 moderates the transcriptional activity of H2A.J, and H2A.J-specific Ser-123 can be phosphorylated in response to DNA damage with potentiation of its transcriptional activity by the phospho-mimetic S123E mutation. Our work demonstrates the functional importance of H2A.J-specific residues and potential mechanisms for its function in promoting inflammatory gene expression in senescence.

scholarly journals Cytokine-mediated β-cell damage in PARP-1-deficient islets

2012 ◽  
Vol 303 (2) ◽  
pp. E172-E179 ◽  
Author(s):  
Teresa Andreone ◽  
Gordon P. Meares ◽  
Katherine J. Hughes ◽  
Polly A. Hansen ◽  
John A. Corbett
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Cell Death ◽  
Insulin Secretion ◽  
Cell Damage ◽  
Β Cell ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Parp 1 ◽  
Deficient Mice

Poly(ADP)-ribose polymerase (PARP) is an abundant nuclear protein that is activated by DNA damage; once active, it modifies nuclear proteins through attachment of poly(ADP)-ribose units derived from β-nicotinamide adenine dinucleotide (NAD+). In mice, the deletion of PARP-1 attenuates tissue injury in a number of animal models of human disease, including streptozotocin-induced diabetes. Also, inflammatory cell signaling and inflammatory gene expression are attenuated in macrophages isolated from endotoxin-treated PARP-1-deficient mice. In this study, the effects of PARP-1 deletion on cytokine-mediated β-cell damage and macrophage activation were evaluated. There are no defects in inflammatory mediator signaling or inflammatory gene expression in macrophages and islets isolated from PARP-1-deficient mice. While PARP-1 deficiency protects islets against cytokine-induced islet cell death as measured by biochemical assays of membrane polarization, the genetic absence of PARP-1 does not effect cytokine-induced inhibition of insulin secretion or cytokine-induced DNA damage in islets. While PARP-1 deficiency appears to provide protection from cell death, it fails to provide protection against the inhibitory actions of cytokines on insulin secretion or the damaging actions on islet DNA integrity.

scholarly journals Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Kévin Contrepois ◽  
Clément Coudereau ◽  
Bérénice A. Benayoun ◽  
Nadine Schuler ◽  
Pierre-François Roux ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Variant ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene
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