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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.

Original publication

DOI

10.1038/s41467-017-02687-7

Type

Journal article

Journal

Nat Commun

Publication Date

17/01/2018

Volume

9

Keywords

Animals, Carcinogenesis, Cells, Cultured, DNA Repair, DNA-Binding Proteins, Humans, Loss of Function Mutation, Melanoma, Methyltransferases, Mice, Mice, Knockout, Proto-Oncogene Proteins B-raf, Ultraviolet Rays