Photoaging is the most component of facial aging, nearly 80%, of which is mainly from UV radiation. There are three types of UV in sunlight characterized by wavelength, UVA, UVB, and UVC17. Since UVC is always blocked by the ozone layer before reaching the earth’s surface, UVA and UVB are commonly used as cell models for photoaging studies. For living cells, the DNA was commonly known as the main target of UV irradiation, and the impaired DNA usually can directly trigger DNA damage18. Compared to UVA, the UVB can induce more CPDs than UVA, but the photoproducts produced by UVA are more mutagenic19. Thus, whatever the UVA and UVB, both their exposure can directly or as a consequence of cellular metabolism form the DNA single- or double-strand and DNA cross-links20. After DNA damage, cellular principally has two outcomes. When DNA damage hampers transcription and replication, cellular functionality is impeded, facilitating cellular senescence and apoptosis. In contrast, if DNA is repaired with mistakes, gives rise to mutations and chromosomal aberrations and promotes cancer development21. Therefore, a network of events, termed the DDR, is in response to DNA damage. The DDR is complex, including “sensor” proteins, “transducer” proteins, and “effector” proteins. In this article, we are mainly concerned with the “effector” proteins, which commonly include DNA repair mechanism, cell cycle checkpoints, cellular senescence, and apoptosis5.
p53, the tumor suppressor, plays a central role in DDR for controlling the cell fate, especially the DNA repair, cellular senescence, and apoptosis22. However, how p53 regulates different cues to choose the cell survival and cell death outcomes remain largely unknown and have been of great interest. Interestingly, p53 can be regulated by multiple mechanisms, including DNA binding modulation influenced by DNA sequence and chromatin structure, post-translational modifications, cofactors interaction, and temporal expression dynamics23. Meanwhile, the “affinity model” studies presented that p53 in cell cycle arrest is expressed at low levels and apoptosis at higher levels24. In our study, we found that the ACTL6A expression played a significant role in the decision-making transcription factor between cellular senescence and apoptosis. UVA and UVB exposure can increase the ACTL6A expression, however, knockdown of the ACTL6A decreased the cellular senescence and increased the apoptosis simultaneously. In addition, ACTL6A deficiency may promoted the p53 expression levels at the same UVR doses, and the gene expression to choose between the competing cellular senescence and apoptosis was also changed.
ACTL6A, also known as BAF53a, Arp4, is an important member of human IN080、TIP60, and mammal SWI/SNF complex25. INO80 participates in the nucleotide excision repair pathway in DNA damage repair and affects the nucleosome reorganization and displacement during repair26. After UV irradiation, we found the ACTL6A was overexpressed in the HDFs or mice. When we knock down the ACTL6A, the cellular senescence of HDFs was alleviated, however, the apoptosis of the HDFs was facilitated. We considered the HDFs lacking ACTL6A to be more sensitive to UV, but they also own normal global UV photoproduct repair kinetics. To identify this hypothesis, we detected the intracellular ROS in each group. Intriguingly, the mean intensity of ROS in the ACTL6A deficiency groups were both decreased. Consistently, the DNA damage foci γ-H2AX were raised after ACTL6A deficiency, and the expression of pro-apoptotic protein Bax were elevated. As we all know, the accumulation of excessive ROS always leads to cellular dysfunction, including cellular senescence and apoptosis. ROS accumulation also can lead to the expression of several metalloproteinases, such as MMP-327. The MMP-3, along with IL-6 are often used as markers of cellular senescence, collectively called SASP. As feedback, the SASP expression contributes to ER stress, eventually activating ROS production and DDR16. In accordance, the MMP-3 and IL-6 production were both significantly reduced after ACTL6A knockdown, however, raised at the ACTL6A overexpression conditions, as in undergoing UVR radio.
In this study, we focused on the cytological level to investigate the role and mechanism of ACTL6A in fibroblast and validated it in animal models. However, further zoological experiments and clinical samples are needed for further exploration. Some studies have shown that MiR-216a-3p can play a certain role by affecting ACTL6A28, which also provides a certain research basis for subsequent clinical transformation and contributes to the treatment progress of UV-induced or UV-needed diseases in the future.