The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease.

Samantha Cialfi,Azzurra Zonfrilli,Gianfranco Biolcati,Carlo De Blasio,Isabella Screpanti,Loredana Le Pera,Claudio Palleschi,Luca Barbieri,Rocco Palermo,Daniela Uccelletti,Claudio Talora,Germano Mariano

doi:10.1038/srep31567

Abstract

Mutation of the Golgi Ca2+-ATPase ATP2C1 is associated with deregulated calcium homeostasis and altered skin function. ATP2C1 mutations have been identified as having a causative role in Hailey-Hailey disease, an autosomal-dominant skin disorder. Here, we identified ATP2C1 as a crucial regulator of epidermal homeostasis through the regulation of oxidative stress. Upon ATP2C1 inactivation, oxidative stress and Notch1 activation were increased in cultured human keratinocytes. Using RNA-seq experiments, we found that the DNA damage response (DDR) was consistently down-regulated in keratinocytes derived from the lesions of patients with Hailey-Hailey disease. Although oxidative stress activates the DDR, ATP2C1 inactivation down-regulates DDR gene expression. We showed that the DDR response was a major target of oxidative stress-induced Notch1 activation. Here, we show that this activation is functionally important because early Notch1 activation in keratinocytes induces keratinocyte differentiation and represses the DDR. These results indicate that an ATP2C1/NOTCH1 axis might be critical for keratinocyte function and cutaneous homeostasis, suggesting a plausible model for the pathological features of Hailey-Hailey disease.

Highlights

Mutation of the Golgi Ca2+-ATPase ATP2C1 is associated with deregulated calcium homeostasis and altered skin function
DNA damage/DNA repair was the main cluster in the enrichment map, and the genes involved in the process were predominantly down-regulated in the lesioned skin of Hailey-Hailey disease (HHD) patients compared with the unaffected controls (Fig. 2 and Supplementary Fig. 1)
The mutation burden we identified in the HHD lesions was greater than those of most other common genetic diseases, as previously described[35]; for example, the mutation burden was comparable to the burden observed in Seckel Syndrome, in which the functional loss of the centrosomal protein CEP152 results in an impairment of DNA damage response (DDR) pathways[35,36]

Summary

Introduction

Mutation of the Golgi Ca2+-ATPase ATP2C1 is associated with deregulated calcium homeostasis and altered skin function. RNA-seq data analysis identified a substantial number of differentially expressed genes in lesioned skin These changes in gene expression were clearly shown by the down-regulation of genes involved in the DDR and the up-regulation of genes related to the inflammatory response. Our hypothesis is that the disturbance of calcium homeostasis in Hailey-Hailey keratinocytes promotes skin lesions by causing DNA damage and that Notch[1] might mediate this response. This signaling can lead to a level of DNA damage that overwhelms the defenses of the keratinocyte cells and causes their death. Our results may contribute to a better characterization of a subset of human skin diseases and guide new therapeutic treatments

Methods

Results

Discussion

Conclusion