Department of Medicine, Section of Dermatology, University of Chicago, Chicago, Illinois, USA.
Committee on Cancer Biology, University of Chicago, Chicago, Illinois, USA.
Photochem Photobiol. 2024 Jul-Aug;100(4):1031-1040. doi: 10.1111/php.13904. Epub 2024 Jan 8.
Ultraviolet B (UVB) radiation represents a major carcinogen for the development of all skin cancer types. Mechanistically, UVB induces damage to DNA in the form of lesions, including cyclobutane pyrimidine dimers (CPDs). Disruption of the functional repair processes, such as nucleotide excision repair (NER), allows persistence of DNA damage and contributes to skin carcinogenesis. Recent work has implicated mA RNA methylation and its regulatory proteins as having critical roles in facilitating UVB-induced DNA damage repair. However, the biological functions of the mA reader YTHDC2 are unknown in this context. Here, we show that YTHDC2 inhibition enhances the repair of UVB-induced DNA damage. We discovered that YTHDC2 inhibition increased the expression of PTEN while it decreased the expression of the PRC2 component SUZ12 and the levels of the histone modification H3K27me3. However, none of these functions were causally linked to the improvements in DNA repair, suggesting that the mechanism utilized by YTHDC2 may be unconventional. Moreover, inhibition of the mA writer METTL14 reversed the effect of YTHDC2 inhibition on DNA repair while inhibition of the mA eraser FTO mimicked the effect of YTHDC2 inhibition, indicating that YTHDC2 may regulate DNA repair through the mA pathway. Finally, compared to normal human skin, YTHDC2 expression was upregulated in human cutaneous squamous cell carcinomas (cSCC), suggesting that it may function as a tumor-promoting factor in skin cancer. Taken together, our findings demonstrate that the mA reader YTHDC2 plays a role in regulating UVB-induced DNA damage repair and may serve as a potential biomarker in cSCC.
紫外线 B（UVB）辐射是所有皮肤癌类型发展的主要致癌因素。从机制上讲，UVB 以损伤的形式诱导 DNA 损伤，包括环丁烷嘧啶二聚体（CPDs）。功能性修复过程（如核苷酸切除修复（NER））的破坏会导致 DNA 损伤的持续存在，并促进皮肤癌变。最近的工作表明，m6A 甲基化及其调节蛋白在促进 UVB 诱导的 DNA 损伤修复中具有关键作用。然而，在这种情况下，mA 阅读器 YTHDC2 的生物学功能尚不清楚。在这里，我们表明 YTHDC2 抑制增强了 UVB 诱导的 DNA 损伤的修复。我们发现 YTHDC2 抑制增加了 PTEN 的表达，同时降低了 PRC2 成分 SUZ12 的表达和组蛋白修饰 H3K27me3 的水平。然而，这些功能都与 DNA 修复的改善没有因果关系，这表明 YTHDC2 可能利用了非常规的机制。此外，mA 书写器 METTL14 的抑制逆转了 YTHDC2 抑制对 DNA 修复的影响，而 mA 擦除器 FTO 的抑制模拟了 YTHDC2 抑制的效果，表明 YTHDC2 可能通过 mA 途径调节 DNA 修复。最后，与正常人类皮肤相比，YTHDC2 在人类皮肤鳞状细胞癌（cSCC）中的表达上调，表明其可能在皮肤癌中作为一种促进肿瘤的因素发挥作用。总之，我们的研究结果表明，mA 阅读器 YTHDC2 在调节 UVB 诱导的 DNA 损伤修复中发挥作用，可能作为 cSCC 的潜在生物标志物。
