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Calcitriol Prevents RAD51 Loss and cGAS-STING-IFN Response Triggered by Progerin.
Proteomics ( IF 3.4 ) Pub Date : 2019-12-30 , DOI: 10.1002/pmic.201800406
Nuria Coll-Bonfill 1 , Rafael Cancado de Faria 1 , Sweta Bhoopatiraju 1 , Susana Gonzalo 1
Affiliation  

Hutchinson Gilford progeria syndrome (HGPS) is a devastating accelerated aging disease caused by LMNA gene mutation. The truncated lamin A protein produced "progerin" has a dominant toxic effect in cells, causing disruption of nuclear architecture and chromatin structure, genomic instability, gene expression changes, oxidative stress, and premature senescence. It was previously shown that progerin-induced genomic instability involves replication stress (RS), characterized by replication fork stalling and nuclease-mediated degradation of stalled forks. RS is accompanied by activation of cGAS/STING cytosolic DNA sensing pathway and STAT1-regulated interferon (IFN)-like response. It is also found that calcitriol, the active hormonal form of vitamin D, rescues RS and represses the cGAS/STING/IFN cascade. Here, the mechanisms underlying RS in progerin-expressing cells and the rescue by calcitriol are explored. It is found that progerin elicits a marked downregulation of RAD51, concomitant with increased levels of phosphorylated-RPA, a marker of RS. Interestingly, calcitriol prevents RS and activation of the cGAS/STING/IFN response in part through maintenance of RAD51 levels in progerin-expressing cells. Thus, loss of RAD51 is one of the consequences of progerin expression that can contribute to RS and activation of the IFN response. Stabilization of RAD51 helps explain the beneficial effects of calcitriol in these processes.

中文翻译:

骨化三醇可防止 Progerin 触发的 RAD51 丢失和 cGAS-STING-IFN 反应。

Hutchinson Gilford 早衰综合症 (HGPS) 是一种由 LMNA 基因突变引起的毁灭性加速衰老疾病。截短的核纤层蛋白 A 产生的“早老素”在细胞中具有显着的毒性作用,导致核结构和染色质结构破坏、基因组不稳定、基因表达变化、氧化应激和过早衰老。先前表明,早老素诱导的基因组不稳定性涉及复制应激(RS),其特征是复制叉停滞和核酸酶介导的停滞叉降解。RS 伴随着 cGAS/STING 胞质 DNA 传感通路的激活和 STAT1 调节的干扰素 (IFN) 样反应。研究还发现,骨化三醇(维生素 D 的活性激素形式)可以拯救 RS 并抑制 cGAS/STING/IFN 级联。在此,探讨了早老素表达细胞中 RS 的机制以及骨化三醇的拯救作用。研究发现,早老素引起 RAD51 显着下调,同时磷酸化 RPA(RS 的标志物)水平增加。有趣的是,骨化三醇部分通过维持早老蛋白表达细胞中的 RAD51 水平来防止 RS 和 cGAS/STING/IFN 反应的激活。因此,RAD51 的缺失是早老蛋白表达的后果之一,可促进 RS 和 IFN 反应的激活。RAD51 的稳定性有助于解释骨化三醇在这些过程中的有益作用。
更新日期:2019-12-30
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