DOT1L在紫外线诱导的黑色素瘤发生中的保护作用。
The protective role of DOT1L in UV-induced melanomagenesis.
作者信息
Zhu Bo, Chen Shuyang, Wang Hongshen, Yin Chengqian, Han Changpeng, Peng Cong, Liu Zhaoqian, Wan Lixin, Zhang Xiaoyang, Zhang Jie, Lian Christine G, Ma Peilin, Xu Zhi-Xiang, Prince Sharon, Wang Tao, Gao Xiumei, Shi Yujiang, Liu Dali, Liu Min, Wei Wenyi, Wei Zhi, Pan Jingxuan, Wang Yongjun, Xuan Zhenyu, Hess Jay, Hayward Nicholas K, Goding Colin R, Chen Xiang, Zhou Jun, Cui Rutao
机构信息
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA.
Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, 250014, Jinan, China.
出版信息
Nat Commun. 2018 Jan 17;9(1):259. doi: 10.1038/s41467-017-02687-7.
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.
DOT1L组蛋白H3赖氨酸79（H3K79）甲基转移酶在MLL重排的白血病发生过程中发挥致癌作用。在此，我们证明，与MLL重排的白血病相反，DOT1L在紫外线辐射（UVR）诱导的黑色素瘤发生中起保护作用。具体而言，DOT1L基因位于人类黑色素瘤中一个经常缺失的区域，并发生体细胞突变。特定突变在功能上损害DOT1L甲基转移酶的酶活性，导致H3K79甲基化减少。重要的是，在缺乏DOT1L的情况下，UVR诱导的DNA损伤修复效率低下，因此DOT1L缺失会促进小鼠在暴露于UVR后发生黑色素瘤。从机制上讲，DOT1L促进DNA损伤修复，甲基化的H3K79参与将XPC结合并募集到DNA损伤位点进行核苷酸切除修复（NER）。这项研究表明，DOT1L在UVR诱导的黑色素瘤发生中起保护作用。
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