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 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.



Leukemia, histone H3 trimethyl Lys4, Methylation, Melanoma, Transgenic mice, DNA damage, Chromatin, Mutation, DOT1L protein

"This work was supported by the National Key R&D Program of China (2017YFA0503502) and the National Natural Science Foundation of China (31730050). This work was also supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Cancer Research Program under Award No. W81XWH-15-1-0109; Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (Grant No.81428025 for R.C.); Major Projects of international Cooperation and Exchanges from National Natural Science Foundation of China (81620108024), and National Natural Science Foundation of China (81572679, 81630106); Innovative Research Team in University of Ministry of Education of China (IRT1270); Microarray was performed by the Boston University Microarray Sequencing Resource (CTSA grant UL1-TR001430).


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