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Apoptosis, the only cell death pathway that can be measured in human diploid dermal fibroblasts following lethal UVB irradiation.

ABSTRACT: Ultraviolet radiation (UVR) is a major environmental genotoxic agent. In skin, it can lead to the formation of mutagenic DNA damage. Several mechanisms are in place to prevent the conversion of these DNA damage into skin cancer-driver mutations. An important mutation prevention mechanism is the programmed cell death, which can safely dispose of the damaged cells. Apoptosis is the most studied and best characterised programmed cell death, but an increasing amount of new cell death pathways are emerging. Using different pharmacological cell death inhibitors and antioxidants, we have evaluated the implication of apoptosis, necroptosis, ferroptosis and parthanatos in UVB-induced cell death in human diploid dermal fibroblasts. Our results show that apoptosis is the only known cell death mechanism induced by UVB irradiation in fibroblasts. We also showed that lethal UVB irradiation induces a PARP-dependent drastic loss of cellular metabolic activity caused by an overused of NAD+.

SUBMITTER: Gary AS

PROVIDER: S-EPMC7609555 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Apoptosis, the only cell death pathway that can be measured in human diploid dermal fibroblasts following lethal UVB irradiation.

Gary Anne-Sophie AS Rochette Patrick J PJ

Scientific reports 20201103 1

Ultraviolet radiation (UVR) is a major environmental genotoxic agent. In skin, it can lead to the formation of mutagenic DNA damage. Several mechanisms are in place to prevent the conversion of these DNA damage into skin cancer-driver mutations. An important mutation prevention mechanism is the programmed cell death, which can safely dispose of the damaged cells. Apoptosis is the most studied and best characterised programmed cell death, but an increasing amount of new cell death pathways are em ...[more]

PMID: 33144600

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Project description:BackgroundCellular senescence can be induced by a variety of extrinsic stimuli, and sustained exposure to sunlight is a key factor in photoaging of the skin. Accordingly, irradiation of skin fibroblasts by UVB light triggers cellular senescence, which is thought to contribute to extrinsic skin aging, although molecular mechanisms are incompletely understood. Here, we addressed molecular mechanisms underlying UVB induced senescence of human diploid fibroblasts.ResultsWe observed a parallel activation of the p53/p21(WAF1) and p16(INK4a)/pRb pathways. Using genome-wide transcriptome analysis, we identified a transcriptional signature of UVB-induced senescence that was conserved in three independent strains of human diploid fibroblasts (HDF) from skin. In parallel, a comprehensive screen for microRNAs regulated during UVB-induced senescence was performed which identified five microRNAs that are significantly regulated during the process. Bioinformatic analysis of miRNA-mRNA networks was performed to identify new functional mRNA targets with high confidence for miR-15a, miR-20a, miR-20b, miR-93, and miR-101. Already known targets of these miRNAs were identified in each case, validating the approach. Several new targets were identified for all of these miRNAs, with the potential to provide new insight in the process of UVB-induced senescence at a genome-wide level. Subsequent analysis was focused on miR-101 and its putative target gene Ezh2. We confirmed that Ezh2 is regulated by miR-101 in human fibroblasts, and found that both overexpression of miR-101 and downregulation of Ezh2 independently induce senescence in the absence of UVB irradiation. However, the downregulation of miR-101 was not sufficient to block the phenotype of UVB-induced senescence, suggesting that other UVB-induced processes induce the senescence response in a pathway redundant with upregulation of miR-101.ConclusionWe performed a comprehensive screen for UVB-regulated microRNAs in human diploid fibroblasts, and identified a network of miRNA-mRNA interactions mediating UVB-induced senescence. In addition, miR-101 and Ezh2 were identified as key players in UVB-induced senescence of HDF.

Dataset Information

Apoptosis, the only cell death pathway that can be measured in human diploid dermal fibroblasts following lethal UVB irradiation.

Publications

Apoptosis, the only cell death pathway that can be measured in human diploid dermal fibroblasts following lethal UVB irradiation.

Similar Datasets

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