ADAR1 induces adenosine-targeted DNA mutations in senescent Bcl6-deficient cells.
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 (CSR) simultaneously induces somatic mutations in an IgM class-switch (Ig-Smu) region of IgG B cells. Surprisingly, mutations were detected in the Ig-Smu region of Bcl6-deficient IgM B cells without CSR, and these mutations were mainly generated by conversion of adenosine to guanosine, suggesting a novel DNA mutator in the B cells. The adenosine deaminase acting on RNA1 (ADAR1) 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.
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