BMAL1 and CLOCK proteins in regulating UVB‐induced apoptosis and DNA damage responses in human keratinocytes

Abstract

A diverse array of biological processes are under circadian controls. In mouse skin, ultraviolet ray (UVR)-induced apoptosis and DNA damage responses are time-of-day dependent, which are controlled by core clock proteins. This study investigates the roles of clock proteins in regulating UVB responses in human keratinocytes (HKCs). We found that the messenger RNA expression of brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) genes is altered by low doses (5 mJ/cm ) of UVB in the immortalized HaCat HKCs cell line. Although depletion of BMAL1 or CLOCK has no effect on the activation of Rad3-related protein kinases-checkpoint kinase 1-p53 mediated DNA damage checkpoints, it leads to suppression of UVB-stimulated apoptotic responses, and downregulation of UVB-elevated expression of DNA damage marker γ-H2AX and cell cycle inhibitor p21. Diminished apoptotic responses are also observed in primary HKCs depleted of BMAL1 or CLOCK after UVB irradiation. While CLOCK depletion shows a suppressive effect on UVB-induced p53 protein accumulation, depletion of either clock gene triggers early keratinocyte differentiation of HKCs at their steady state. These results suggest that UVB-induced apoptosis and DNA damage responses are controlled by clock proteins, but via different mechanisms in the immortalized human adult low calcium temperature and primary HKCs. Given the implication of UVB in photoaging and photocarcinogenesis, mechanistic elucidation of circadian controls on UVB effects in human skin will be critical and beneficial for prevention and treatment of skin cancers and other skin-related diseases.

The Anti-Ageing and Whitening Potential of a Cosmetic Serum Containing 3-O-ethyl-l-ascorbic Acid

“…The effect of UVB rays on the DNA damage of skin cells was evaluated in association with a pre-treatment of the product to investigate a photoprotective effect. The phosphorylation of histone H2AX (γ-H2AX) is a direct index of DNA molecular lesion [ 30 ] and it plays an important role in the DNA repair process. Therefore, damage to the keratinocytes’ DNA was determined by an immunofluorescence analysis of γ-H2AX positive cells.…”

Circadian Rhythms Within the Female HPG Axis: From Physiology to Etiology

“…A recent study confirmed that hyperinsulinemia and hyperandrogenism share a bidirectional link, and both of them promote abnormal clock gene expression and induce granulosa cell apoptosis ( 65 ). Despite the relationship between circadian rhythm and apoptosis having been revealed in multiple cell types ( 81 , 82 ), few studies have focused on ovarian granulosa cells ( Fig. 2 ; Table 1 ).…”

Circadian Clocks and Cancer: Timekeeping Governs Cellular Metabolism

“…This data suggests differential roles of the clock proteins in regulating p53. These differences in p53 activity linked to the clock could be attributed to the multiple functions of p53 linked to UV stress, DNA damage response, DNA repair, or apoptosis pathways in a cell type dependent manner [63–66].…”