title: ADAR1 protein induces adenosine-targeted DNA mutations in senescent Bcl6 gene-deficient cells.
abstract: Somatic mutations accumulate in senescent cells. Bcl6, which functions as a transcriptional repressor, has been identified as a potent inhibitor of cell senescence, but a role of Bcl6 in the accumulation of somatic mutations has remained unclear. Ig class-switch recombination simultaneously induces somatic mutations in an IgM class-switch (Ig-Sμ) region of IgG B cells. Surprisingly, mutations were detected in the Ig-Sμ region of Bcl6-deficient IgM B cells without class-switch recombination, and these mutations were mainly generated by conversion of adenosine to guanosine, suggesting a novel DNA mutator in the B cells. The ADAR1 (adenosine deaminase acting on RNA1) gene was overexpressed in Bcl6-deficient cells, and its promoter analysis revealed that ADAR1 is a molecular target of Bcl6. Exogenous ADAR1 induced adenosine-targeted DNA mutations in IgM B cells from ADAR1-transgenic mice and in wild-type mouse embryonic fibroblasts (MEFs). These mutations accumulated in senescent MEFs accompanied with endogenous ADAR1 expression, and the frequency in senescent Bcl6-deficient MEFs was higher than senescent wild-type MEFs. Thus, Bcl6 protects senescent cells from accumulation of adenosine-targeted DNA mutations induced by ADAR1.
authors.affiliation: Department of Developmental Genetics (H2), School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Tsuruoka
authors.forename: Masafumi
authors.initials: M
authors.lastname: Arima
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yoshida
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.forename: Akemi
authors.initials: A
authors.lastname: Sakamoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hatano
authors.forename: Hisae
authors.initials: H
authors.lastname: Satake
authors.forename: Eggi
authors.initials: E
authors.lastname: Arguni
authors.forename: Ji-Yang
authors.initials: JY
authors.lastname: Wang
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Yang
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nishikura
authors.forename: Souei
authors.initials: S
authors.lastname: Sekiya
authors.forename: Makio
authors.initials: M
authors.lastname: Shozu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokuhisa
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D051560:Proto-Oncogene Proteins c-bcl-6; D016601:RNA-Binding Proteins
chemical_list: C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D016601:RNA-Binding Proteins; D004247:DNA; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D000241:Adenosine