Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-017-02687-7
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Funding
- National Key R&D Program of China [2017YFA0503502]
- National Natural Science Foundation of China [31730050, 81572679, 81630106]
- Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Cancer Research Program [W81XWH-15-1-0109]
- Melanoma Research Foundation Establish Investigator Award
- Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China [81428025]
- Major Projects of international Cooperation and Exchanges from National Natural Science Foundation of China [81620108024]
- Innovative Research Team in University of Ministry of Education of China [IRT1270]
- NHMRC
- Ludwig Institute for Cancer Research
- CTSA [UL1-TR001430]
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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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