title: Recruitment of cyclin G2 to promyelocytic leukemia nuclear bodies promotes dephosphorylation of γH2AX following treatment with ionizing radiation.
abstract: Cyclin G2 (CycG2) and Cyclin G1 (CycG1), two members of the Cyclin G subfamily, share high amino acid homology in their Cyclin G boxes. Functionally, they play a common role as association partners of the B'γ subunit of protein phosphatase 2A (PP2A) and regulate PP2A function, and their expression is increased following DNA damage. However, whether or not CycG1 and CycG2 have distinct roles during the cellular DNA damage response has remained unclear. Here, we report that CycG2, but not CycG1, co-localized with promyelocytic leukemia (PML) and γH2AX, forming foci following ionizing radiation (IR), suggesting that CycG2 is recruited to sites of DNA repair and that CycG1 and CycG2 have distinct functions. PML failed to localize to nuclear foci when CycG2 was depleted, and vice versa. This suggests that PML and CycG2 mutually influence each other's functions following IR. Furthermore, we generated CycG2-knockout (Ccng2 (-/-) ) mice to investigate the functions of CycG2. These mice were born healthy and developed normally. However, CycG2-deficient mouse embryonic fibroblasts displayed an abnormal response to IR. Dephosphorylation of γH2AX and checkpoint kinase 2 following IR was delayed in Ccng2 (-/-) cells, suggesting that DNA damage repair may be perturbed in the absence of CycG2. Although knockdown of B'γ in wild-type cells also delayed dephosphorylation of γH2AX, knockdown of B'γ in Ccng2 (-/-) cells prolonged this delay, suggesting that CycG2 cooperates with B'γ to dephosphorylate γH2AX. Taken together, we conclude that CycG2 is localized at DNA repair foci following DNA damage, and that CycG2 regulates the dephosphorylation of several factors necessary for DNA repair.
authors: Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Suita City, Osaka, Japan.
authors: Yoko
authors: Y
authors: Naito
authors: Norikazu
authors: N
authors: Yabuta
authors: Jun
authors: J
authors: Sato
authors: Shouichi
authors: S
authors: Ohno
authors: Muneki
authors: M
authors: Sakata
authors: Takashi
authors: T
authors: Kasama
authors: Masahito
authors: M
authors: Ikawa
authors: Hiroshi
authors: H
authors: Nojima
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D056766:Cyclin G1 / Q000378:metabolism; D056767:Cyclin G2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D000071156:Promyelocytic Leukemia Protein; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D064447:Checkpoint Kinase 2; D056766:Cyclin G1; D056767:Cyclin G2; D006657:Histones; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D054648:Protein Phosphatase 2; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C534703:Ccng1 protein, mouse; C513293:Pml protein, mouse; C485589:Ppp2r5c protein, mouse; C475961:gamma-H2AX protein, mouse
keywords: Cyclin G2; DNA damage; PML; PP2A B'γ; γH2AX
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