The protective role of DOT1L in UV-induced melanomagenesis

Bo Zhu, Shuyang Chen, Hongshen Wang, Chengqian Yin, Changpeng Han, Cong Peng, Zhaoqian Liu, Lixin Wan, Xiaoyang Zhang, Jie Zhang, Christine G. Lian, Peilin Ma, Zhi-xiang Xu, Sharon Prince, Tao Wang, Xiumei Gao, Yujiang Shi, Dali Liu, Min Liu, Wenyi Wei, Zhi Wei, Jingxuan Pan, Yongjun Wang, Zhenyu Xuan, Jay Hess, Nicholas K. Hayward, Colin R. Goding, Xiang Chen (), Jun Zhou () and Rutao Cui ()
Additional contact information
Bo Zhu: Boston University School of Medicine
Shuyang Chen: Boston University School of Medicine
Hongshen Wang: Boston University School of Medicine
Chengqian Yin: Boston University School of Medicine
Changpeng Han: Boston University School of Medicine
Cong Peng: Central South University
Zhaoqian Liu: Central South University
Lixin Wan: H. Lee Moffitt Cancer Center and Research Institute
Xiaoyang Zhang: Dana-Farber Cancer Institute
Jie Zhang: New Jersey Institute of Technology
Christine G. Lian: Harvard Medical School
Peilin Ma: Indiana University School of Medicine
Zhi-xiang Xu: University of Alabama at Birmingham School of Medicine
Sharon Prince: University of Cape Town
Tao Wang: Tianjin University of Traditional Chinese Medicine
Xiumei Gao: Tianjin University of Traditional Chinese Medicine
Yujiang Shi: Harvard Medical School
Dali Liu: Loyola University Chicago
Min Liu: Shandong Normal University
Wenyi Wei: Harvard Medical School
Zhi Wei: New Jersey Institute of Technology
Jingxuan Pan: Jinan University
Yongjun Wang: Shanghai University of Traditional Chinese Medicine
Zhenyu Xuan: University of Texas at Dallas
Jay Hess: Indiana University School of Medicine
Nicholas K. Hayward: QIMR Berghofer Medical Research Institute
Colin R. Goding: University of Oxford
Xiang Chen: Central South University
Jun Zhou: Shandong Normal University
Rutao Cui: Boston University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-02687-7

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