The protective role of DOT1L in UV-induced melanomagenesis

The protective role of DOT1L in UV-induced melanomagenesis

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 gen...

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التفاصيل البيبلوغرافية
المؤلفون الرئيسيون: Zhu, B, Chen, S, Wang, H, Yin, C, Han, C, Peng, C, Liu, Z, Wan, L, Zhang, X, Zhang, J, Lian, C, Ma, P, Xu, Z, 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, N, Goding, C, Chen, X, Zhou, J, Cui, R
التنسيق: Journal article
اللغة:English
منشور في: Springer Nature 2018
الوصف
الملخص: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.

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