Zhu, BoChen, ShuyangWang, HongshenYin, ChengqianHan, ChangpengPeng, CongLiu, ZhaoqianWan, LixinZhang, ZhangZhang, JieLian, Christine G.Ma, PeilinXu, Zhi-xiangPrince, SharonWang, TaoGao, XiumeiShi, YujiangLiu, DaliLiu, MinWei, WenyiWei, ZhiPan, JingxuanWang, YongjunXuan, ZhenyuHess, Jay L.Hayward, Nicholas K.Goding, Colin R.Chen, XiangZhou, JunCui, Rutao2018-05-302018-05-302018-01-17Zhu, B., Chen, S., Wang, H., Yin, C., Han, C., Peng, C., … Cui, R. (2018). The protective role of DOT1L in UV-induced melanomagenesis. Nature Communications, 9, 259. http://doi.org/10.1038/s41467-017-02687-7https://hdl.handle.net/1805/16306The 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.en-USAttribution 3.0 United StatesCarcinogenesisCells, CulturedDNA repairDNA-binding proteinsLoss of function mutationMelanomaMethyltransferasesProto-oncogene proteins B-rafUltraviolet raysArticle