The protective role of DOT1L in UV-induced melanomagenesis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-01-17

AUTHORS

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, Rutao Cui

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. More... »

PAGES

259

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  • Journal

    TITLE

    Nature Communications

    ISSUE

    1

    VOLUME

    9

    Author Affiliations

  • Shandong Provincial Key Laboratory of Animal Resistance Biology, Institute of Biomedical Sciences, College of Life Sciences, Shandong Normal University, 250014, Jinan, China
  • Department of Dermatology & China Hunan key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, 410008, Changsha, China
  • Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, China
  • Institute of Life Science, Jiangsu University, 212013, Zhenjiang, China
  • Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, 33612, Tampa, FL, USA
  • Dana-Farber Cancer Institute, 450 Brookline Avenue, 02215, Boston, MA, USA
  • Department of Computer Science, New Jersey Institute of Technology, 07102, Newark, NJ, USA
  • Department of Pathology, The Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, 02115, Boston, MA, USA
  • Department of Pathology, Indiana University School of Medicine, 340 West 10th Street, Fairbanks 6200, 46202, Indianapolis, IN, USA
  • Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham School of Medicine, 35233, Birmingham, AL, USA
  • Department of Human Biology, University of Cape Town, 7700, Rondebosch, Cape Town, South Africa
  • Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 300193, Tianjin, China
  • Department of Medicine, Endocrinology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, 02115, Boston, MA, USA
  • Department of Chemistry and Biochemistry, Loyola University Chicago, 60660, Chicago, IL, USA
  • Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 02115, Boston, MA, USA
  • Cancer Pharmacology Research Institute, Jinan University, 510632, Guangzhou, China
  • Department of Biological Sciences, Center for Systems Biology, University of Texas at Dallas, 75080, Richardson, TX, USA
  • QIMR Berghofer Medical Research Institute, 4006, Brisbane City, QLD, Australia
  • Ludwig Institute for Cancer Research, University of Oxford, Headington, OX3 7DQ, Oxford, UK
  • Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 02118, Boston, MA, USA
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-017-02687-7

    DOI

    http://dx.doi.org/10.1038/s41467-017-02687-7

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1100320497

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29343685


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