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J Biol Chem. 2013 Jan 11;288(2):826-36. doi: 10.1074/jbc.M112.365718. Epub 2012 Dec 3.

ADAR1 protein induces adenosine-targeted DNA mutations in senescent Bcl6 gene-deficient cells.

Author information

  • 1Department of Developmental Genetics (H2), School of Medicine, Chiba University, Chiba 260-8670, Japan.

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.

PMID:
23209284
[PubMed - indexed for MEDLINE]
PMCID:
PMC3543032
Free PMC Article

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