The DOT1L histone H3 lysine 79 (H3K79) methyltransferase plays an oncogenic role in MLL-rearranged leukemogenesis. Here, we demonstrate that, in contrast to MLL-rearranged leukemia, DOT1L plays a protective role in ultraviolet radiation (UVR)-induced melanoma development. Specifically, the DOT1L gene is located in a frequently deleted region and undergoes somatic mutation in human melanoma. Specific mutations functionally compromise DOT1L methyltransferase enzyme activity leading to reduced H3K79 methylation. Importantly, in the absence of DOT1L, UVR-induced DNA damage is inefficiently repaired, so that DOT1L loss promotes melanoma development in mice after exposure to UVR. Mechanistically, DOT1L facilitates DNA damage repair, with DOT1L-methylated H3K79 involvement in binding and recruiting XPC to the DNA damage site for nucleotide excision repair (NER). This study indicates that DOT1L plays a protective role in UVR-induced melanomagenesis.

中文翻译：

---

DOT1L 在紫外线诱导的黑色素瘤形成中的保护作用。

DOT1L 组蛋白 H3 赖氨酸 79 (H3K79) 甲基转移酶在 MLL 重排白血病发生中起致癌作用。在这里，我们证明，与 MLL 重排白血病相比，DOT1L 在紫外线辐射 (UVR) 诱导的黑色素瘤发展中起保护作用。具体而言，DOT1L 基因位于人类黑色素瘤中经常缺失的区域并发生体细胞突变。特定突变在功能上损害 DOT1L 甲基转移酶活性，导致 H3K79 甲基化减少。重要的是，在没有 DOT1L 的情况下，UVR 诱导的 DNA 损伤无法有效修复，因此 DOT1L 的缺失会促进小鼠暴露于 UVR 后黑色素瘤的发展。从机制上讲，DOT1L 促进 DNA 损伤修复，DOT1L-甲基化 H3K79 参与结合和招募 XPC 到 DNA 损伤位点以进行核苷酸切除修复 (NER)。该研究表明 DOT1L 在 UVR 诱导的黑色素瘤形成中起保护作用。