TY - JOUR
T1 - The protective role of DOT1L in UV-induced melanomagenesis
AU - Zhu, Bo
AU - Chen, Shuyang
AU - Wang, Hongshen
AU - Yin, Chengqian
AU - Han, Changpeng
AU - Peng, Cong
AU - Liu, Zhaoqian
AU - Wan, Lixin
AU - Zhang, Xiaoyang
AU - Zhang, Jie
AU - Lian, Christine G.
AU - Ma, Peilin
AU - Xu, Zhi Xiang
AU - Prince, Sharon
AU - Wang, Tao
AU - Gao, Xiumei
AU - Shi, Yujiang
AU - Liu, Dali
AU - Liu, Min
AU - Wei, Wenyi
AU - Wei, Zhi
AU - Pan, Jingxuan
AU - Wang, Yongjun
AU - Xuan, Zhenyu
AU - Hess, Jay
AU - Hayward, Nicholas K.
AU - Goding, Colin R.
AU - Chen, Xiang
AU - Zhou, Jun
AU - Cui, Rutao
N1 - Funding Information:
We thank Dr. Yi Zhang (Harvard and HHMI) and Dr. Guo Wei (The Broad Institute) for reagents and helpful suggestion. This work was supported by the National Key R&D Program of China (J.Z., 2017YFA0503502) and the National Natural Science Foundation of China (J.Z., 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, Melanoma Research Foundation Establish Investigator Award (R.C.), 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 (X.C., 81620108024), and National Natural Science Foundation of China (C.P.,81572679, X.G., 81630106). H.W. was supported by Innovative Research Team in University of Ministry of Education of China (IRT1270). R.C. and W.W. are American Cancer Society Research Scholars. N.H. is supported by a Senior Principal Research Fellowship from the NHMRC, and C.R.G. is funded by the Ludwig Institute for Cancer Research. Microarray was performed by the Boston University Microarray Sequencing Resource (CTSA grant UL1-TR001430).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-017-02687-7
DO - 10.1038/s41467-017-02687-7
M3 - Article
C2 - 29343685
AN - SCOPUS:85041386453
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 259
ER -