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.
[Show abstract][Hide abstract] ABSTRACT: Adenosine deaminases acting on RNA (ADARs) are involved in RNA editing that converts adenosine residues to inosine specifically in double-stranded RNAs (dsRNA). This A-to-I RNA editing pathway and the RNA interference (RNAi) pathway seem to interact antagonistically by competing for their common dsRNA substrates. For instance, A-to-I editing of certain microRNA (miRNA) precursors by ADAR1 and ADAR2 inhibits their processing to mature miRNAs. Recent studies unexpectedly revealed the presence of a completely different type of interaction between the RNA editing mechanism and the RNAi machinery. ADAR1 forms a complex via direct protein-protein interaction with Dicer, an RNase III gene family member involved in the RNAi mechanism. ADAR1 in the Dicer complex promotes pre-miRNA cleavage by Dicer and facilitates loading of miRNA onto RNA-induced silencing complexes, giving rise to an unsuspected stimulative function of ADAR1 on miRNA processing and RNAi mechanisms. ADAR1 differentiates its functions in RNA editing and RNAi by formation of either ADAR1-ADAR1 homodimer or Dicer-ADAR1 heterodimer complexes. Expression of miRNAs is globally inhibited in ADAR1-null mouse embryos, which, in turn, alters expression of their target genes and may contribute to their embryonic lethal phenotype.
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