The protective role of DOT1L in UV-induced melanomagenesis.
Zhu B., Chen S., Wang H., Yin C., Han C., Peng C., Liu Z., Wan L., Zhang X., Zhang J., Lian CG., Ma P., Xu Z-X., Prince S., Wang T., Gao X., Shi Y., Liu D., Liu M., Wei W., Wei Z., Pan J., Wang Y., Xuan Z., Hess J., Hayward NK., Goding CR., Chen X., Zhou J., Cui R.
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.