title: Critical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair.
abstract: The presence of phosphorylated histone H2AX (γ-H2AX) is associated with the local activation of DNA-damage repair pathways. Although γ-H2AX deregulation in cancer has previously been reported, the molecular mechanism involved and its relationship with other histone modifications remain largely unknown. Here we find that the histone methyltransferase SUV39H2 methylates histone H2AX on lysine 134. When H2AX was mutated to abolish K134 methylation, the level of γ-H2AX became significantly reduced. We also found lower γ-H2AX activity following the introduction of double-strand breaks in Suv39h2 knockout cells or on SUV39H2 knockdown. Tissue microarray analyses of clinical lung and bladder tissues also revealed a positive correlation between H2AX K134 methylation and γ-H2AX levels. Furthermore, introduction of K134-substituted histone H2AX enhanced radio- and chemosensitivity of cancer cells. Overall, our results suggest that H2AX methylation plays a role in the regulation of γ-H2AX abundance in cancer.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, Illinois 60637, USA.
authors.forename: Kenbun
authors.initials: K
authors.lastname: Sone
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, Illinois 60637, USA.
authors.forename: Lianhua
authors.initials: L
authors.lastname: Piao
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, Illinois 60637, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakakido
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, D-79108 Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenuwein
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, Illinois 60637, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: 1] Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, Illinois 60637, USA [2] Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
mesh_terms: D000818:Animals; D019556:COS Cells; D002469:Cell Separation; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000737:chemistry; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005720:Gamma Rays; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry*; D008745:Methylation; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: D002843:Chromatin; D006657:Histones; D034741:RNA, Small Interfering; D008239:Lysine