title: RAD18 activates the G2/M checkpoint through DNA damage signaling to maintain genome integrity after ionizing radiation exposure.
abstract: The ubiquitin ligase RAD18 is involved in post replication repair pathways via its recruitment to stalled replication forks, and its role in the ubiquitylation of proliferating cell nuclear antigen (PCNA). Recently, it has been reported that RAD18 is also recruited to DNA double strand break (DSB) sites, where it plays novel functions in the DNA damage response induced by ionizing radiation (IR). This new role is independent of PCNA ubiquitylation, but little is known about how RAD18 functions after IR exposure. Here, we describe a role for RAD18 in the IR-induced DNA damage signaling pathway at G2/M phase in the cell cycle. Depleting cells of RAD18 reduced the recruitment of the DNA damage signaling factors ATM, γH2AX, and 53BP1 to foci in cells at the G2/M phase after IR exposure, and attenuated activation of the G2/M checkpoint. Furthermore, depletion of RAD18 increased micronuclei formation and cell death following IR exposure, both in vitro and in vivo. Our data suggest that RAD18 can function as a mediator for DNA damage response signals to activate the G2/M checkpoint in order to maintain genome integrity and cell survival after IR exposure.
authors: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors: Megumi
authors: M
authors: Sasatani
authors: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors: Yanbin
authors: Y
authors: Xu
authors: Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors: Hidehiko
authors: H
authors: Kawai
authors: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors: Lili
authors: L
authors: Cao
authors: Institute of Molecular Embryology and Genetics (IMEG), Kumamoto University, 2-2-1, Honjo, Kumamoto, 860-0811, Japan.
authors: Satoshi
authors: S
authors: Tateishi
authors: Department of Environmental Health, National Institute of Public Health, 2-3-6, Minami, Wako, Saitama, 351-0197, Japan.
authors: Tsutomu
authors: T
authors: Shimura
authors: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors: Jianxiang
authors: J
authors: Li
authors: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors: Daisuke
authors: D
authors: Iizuka
authors: Department of Genetics, Radiation Effects Research Foundation, 5-2, hijiyamako-en, Minami-ku, Hiroshima, 732-0815, Japan.
authors: Asao
authors: A
authors: Noda
authors: Department of Genetics, Radiation Effects Research Foundation, 5-2, hijiyamako-en, Minami-ku, Hiroshima, 732-0815, Japan.
authors: Kanya
authors: K
authors: Hamasaki
authors: Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, 5-2, hijiyamako-en, Minami-ku, Hiroshima, 732-0815, Japan.
authors: Yoichiro
authors: Y
authors: Kusunoki
authors: Department of Experimental Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors: Kenji
authors: K
authors: Kamiya
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D004249:DNA Damage / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints / Q000528:radiation effects*; D042822:Genomic Instability / Q000528:radiation effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D048629:Micronuclei, Chromosome-Defective / Q000528:radiation effects; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects*; D060168:Thymocytes / Q000378:metabolism / Q000528:radiation effects; D044767:Ubiquitin-Protein Ligases
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C485954:RAD18 protein, human; D044767:Ubiquitin-Protein Ligases