title: AKT phosphorylates H3-threonine 45 to facilitate termination of gene transcription in response to DNA damage.
abstract: Post-translational modifications of core histones affect various cellular processes, primarily through transcription. However, their relationship with the termination of transcription has remained largely unknown. In this study, we show that DNA damage-activated AKT phosphorylates threonine 45 of core histone H3 (H3-T45). By genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) analysis, H3-T45 phosphorylation was distributed throughout DNA damage-responsive gene loci, particularly immediately after the transcription termination site. H3-T45 phosphorylation pattern showed close-resemblance to that of RNA polymerase II C-terminal domain (CTD) serine 2 phosphorylation, which establishes the transcription termination signal. AKT1 was more effective than AKT2 in phosphorylating H3-T45. Blocking H3-T45 phosphorylation by inhibiting AKT or through amino acid substitution limited RNA decay downstream of mRNA cleavage sites and decreased RNA polymerase II release from chromatin. Our findings suggest that AKT-mediated phosphorylation of H3-T45 regulates the processing of the 3' end of DNA damage-activated genes to facilitate transcriptional termination.
authors: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors: Jong-Hyuk
authors: JH
authors: Lee
authors: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors: Byung-Hee
authors: BH
authors: Kang
authors: Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 410-769, Republic of Korea.
authors: Hyonchol
authors: H
authors: Jang
authors: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors: Tae Wan
authors: TW
authors: Kim
authors: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors: Jinmi
authors: J
authors: Choi
authors: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors: Sojung
authors: S
authors: Kwak
authors: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors: Jungwon
authors: J
authors: Han
authors: College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors: Eun-Jung
authors: EJ
authors: Cho
authors: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence and Technology, Seoul National University, Seoul 110-799, Republic of Korea hdyoun@snu.ac.kr.
authors: Hong-Duk
authors: HD
authors: Youn
mesh_terms: D002460:Cell Line; D004249:DNA Damage; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism; D024363:Transcription Initiation Site; D061806:Transcription Termination, Genetic
chemical_list: D006657:Histones; D013912:Threonine; D051057:Proto-Oncogene Proteins c-akt