组蛋白中赖氨酸甲基化是一种翻译后修饰系统，对基因表达产生深远影响，其中组蛋白H3的第79位赖氨酸（H3K79）发生甲基化标志是一个进化上保守的区域，H3K79的甲基化在细胞DNA损伤的修复以及在细胞周期当中发挥了重要的作用。近些年来研究发现DOT1L可使H3K79发生甲基化，且它是唯一一个已知的H3K79的甲基转移酶，DOT1L参与干细胞及组织系统的分化和发育，并且DOT1L的异常表达与肿瘤的发生和预后也密切相关。已有的研究显示DOT1L的异常表达是导致混合系白血病阳性急性白血病预后不良的原因之一，在其他的实体肿瘤中也可检测到DOT1L的异常表达。针对DOT1L异常表达的抑制剂也已进入临床试验阶段，进一步说明了DOT1L的重要性。作者将对DOT1L在正常细胞以及肿瘤细胞中发挥的作用进行综述。

[1] NGUYEN A T,ZHANG Y.The diverse functions of Dot1 and H3K79 methylation[J].Genes & Development,2011,25(13):1345-1358.
[2] VLAMING H,VAN LEEUWEN F.The upstreams and downstreams of H3K79 methylation by DOT1L[J].Chromosoma,2016,125(4):593-605.
[3] MCLEAN C M,KAREMAKER I D,VAN LEEUWEN F.The emerging roles of DOT1L in leukemia and normal development[J].Leukemia,2014,28(11):2131-2138.
[4] GREER E L,SHI Y.Histone methylation:a dynamic mark in health,disease and inheritance[J].Nature Reviews Genetics,2012,13(5):343-357.
[5] KATHERINE W,MICHAEL T,SHONA M.DOT1L and H3K79 methylation in transcription and genomic stability[J].Biomolecules,2018,8(1):11.
[6] LI Y,WEN H,XI Y,et al.AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation[J].Cell,2014,159(3):558-571.
[7] VAN WELSEM T,KORTHOUT T,EKKEBUS R,et al.Dot1 promotes H2B ubiquitination by a methyltransferase-independent mechanism[J].Nucleic Acids Res,2018,46(21):11251-11261.
[8] BOVIO P P,FRANZ H,HEIDRICH S,et al.Differential methylation of H3K79 reveals DOT1L target genes and function in the cerebellum in vivo[J].Molecular Neurobiology,2019,56(6):4273-4287.
[9] FRANZ H,VILLARREAL A,HEIDRICH S,et al.DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex[J].Nucleic Acids Res,2019,47(1):168-183.
[10] MATSUURA K,FUJIMOTO K,DAS B,et al.Histone H3K79 methyltransferase DOT1L is directly activated by thyroid hormone receptor during Xenopusmetamorphosis[J].Cell Bioscience,2012,2(1):25.
[11] CATTANEO P,KUNDERFRANCO P,GRECO C,et al.DOT1L-mediated H3K79me2 modification critically regulates gene expression during cardiomyocyte differentiation[J].Cell Death and Differentiation,2016,23(4):555-564.
[12] YANG D,XUE W,QIANG Z,et al.DOT1L promotes angiogenesis through cooperative regulation of VEGFR2 with ETS-1[J].Oncotarget,2016,7(43):69674-69687.
[13] FENG Y,YANG Y,ORTEGA M M,et al.Early mammalian erythropoiesis requires the DOT1L methyltransferase[J].Blood,2010,116(22):4483-4491.
[14] BREINDEL J L,SKIBINSKI A,SEDIC M,et al.Epigenetic reprogramming of lineage-committed human mammary epithelial cells requires DNMT3A and loss of DOT1L[J].Stem Cell Reports,2017,9(3):943-955.
[15] MONTEAGUDO S,CORNELIS F M F,AZNAR-LOPEZ C,et al.DOT1L safeguards cartilage homeostasis and protects against osteoarthritis[J].Nature Communications,2017,8:15889.
[16] HO L L,SINHA A,VERZI M,et al.DOT1L-mediated H3K79 methylation in chromatin is dispensable for Wnt pathway-specific and other intestinal epithelial functions[J].Molecular and Cellular Biology,2013,33(9):1735-1745.
[17] KIM W,CHOI M,KIM J E.The histone methyltransferase Dot1/DOT1L as a critical regulator of the cell cycle[J].Cell Cycle,2014,13(5):726-738.
[18] KIM W,KIM R,PARK G,et al.Deficiency of H3K79 histone methyltransferase Dot1-like protein (DOT1L) inhibits cell proliferation[J].J Biol Chem,2012,287(8):5588-5599.
[19] BUECHELE C,BREESE E H,SCHNEIDAWIND D,et al.MLL leukemia induction by genome editing of human CD34+ hematopoietic cells[J].Blood,2015,126(14):1683-1694.
[20] YOUNGUK S,BO-RUI C,ANIRUDDHA D.Epigenetic regulators in the development,maintenance,and therapeutic targeting of acute myeloid leukemia[J].Frontiers in Oncology,2018,8:41.
[21] CHANG M J,WU H,ACHILLE N J,et al.Histone H3 lysine 79 methyltransferase Dot1 is required for immortalization by MLL oncogenes[J].Cancer Research,2010,70(24):10234-10242.
[22] KUNTIMADDI A,ACHILLE N,THORPE J,et al.Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and Tri-methylation on target genes and transformation potential[J].Cell Reports,2015,11(5):808-820.
[23] GERMANA C,ELVIRA P,UGO T.Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy[J].Oncotargets and Therapy,2017,11:131-155.
[24] WATER S,NIGEL J.Preclinical pharmacokinetics and pharmacodynamics of pinometostat (EPZ-5676),a first-in-class,small molecule S-adenosyl methionine competitive inhibitor of DOT1L[J].European Journal of Drug Metabolism and Pharmacokinetics,2017,42(6):891-901.
[25] STEIN E M,GARCIA-MANERO G,RIZZIERI D A,et al.The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia[J].Blood,2018,131(24):2661-2669.
[26] SKUCHA A,EBNER J,JOHANNES SCHMÖLLERL,et al.MLL-fusion-driven leukemia requires SETD2 to safeguard genomic integrity[J].Nature Communications,2018,9(1):1983.
[27] LIU Y,GUO J Z,LIU Y,et al.Nuclear lactate dehydrogenase A senses ROS to produce alpha-hydroxybutyrate for HPV-induced cervical tumor growth[J].Nat Commun,2018,9(1):4429.
[28] KRYCZEK I,LIN Y,NAGARSHETH N,et al.IL-22+CD4+ T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L[J].Immunity,2014,40(5):772-784.
[29] LIU D,ZHANG X X,LI M C,et al.C/EBPβ enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation[J].Nature Communications,2018,9(1):1739.
[30] CHEN Y C,LIU X R,LI Y K,et al.Lung cancer therapy targeting histone methylation:opportunities and challenges[J].Computational and Structural Biotechnology Journal,2018,16:211-223.
[31] BOURGUIGNON L Y W,WONG G,SHIINA M.Up-regulation of histone methyltransferase,DOT1L,by matrix hyaluronan promotes microRNA-10 expression leading to tumor cell invasion and chemoresistance in cancer stem cells from head and neck squamous cell carcinoma[J].Biol Chem,2016,291(20):10571-10585.
[32] ZHU B,CHEN S,WANG H,et al.The protective role of DOT1L in UV-induced melanomagenesis[J].Nature Communications,2018,9(1):259.
[33] MARCOS-VILLAR L,DÍAZ-COLUNGA J,SANDOVAL J,et al.Epigenetic control of influenza virus:role of H3K79 methylation in interferon-induced antiviral response[J].Scientific Reports,2018,8(1):1230.
[34] WEI S H,LI C X,YIN Z N,et al.Histone methylation in DNA repair and clinical practice:new findings during the past 5-years[J].Journal of Cancer,2018,9(12):2072-2081.
[35] KAGOYA Y,NAKATSUGAWA M,SASO K,et al.DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models[J].Nature Communications,2018,9(1):1915.