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

Area of Science:

• Molecular Biology
• Genetics
• Cellular senescence

Background:

• Somatic mutations are known to accumulate in senescent cells.
• Bcl6 is a transcriptional repressor that inhibits cell senescence.
• The role of Bcl6 in somatic mutation accumulation was previously unclear.

Purpose of the Study:

• To investigate the role of Bcl6 in somatic mutation accumulation.
• To identify the mechanism behind novel DNA mutations observed in Bcl6-deficient B cells.
• To determine if Bcl6 influences ADAR1 activity in senescent cells.

Main Methods:

• Analysis of Ig class-switch recombination and somatic mutations in Bcl6-deficient IgM B cells.
• Gene expression analysis of ADAR1 in Bcl6-deficient cells.
• Reporter assays to confirm ADAR1 as a molecular target of Bcl6.
• Induction of mutations using exogenous ADAR1 in mouse models and cell lines.
• Comparison of mutation accumulation in senescent wild-type and Bcl6-deficient MEFs.

Main Results:

• Bcl6-deficient IgM B cells accumulated adenosine-to-guanosine mutations without class-switch recombination.
• ADAR1 (adenosine deaminase acting on RNA1) was overexpressed in Bcl6-deficient cells.
• ADAR1 was identified as a direct molecular target of Bcl6.
• Exogenous ADAR1 induced adenosine-targeted DNA mutations in various cell types.
• Mutation accumulation was higher in senescent Bcl6-deficient MEFs compared to senescent wild-type MEFs.

Conclusions:

• Bcl6 acts as a repressor of ADAR1, preventing adenosine-targeted DNA mutations.
• Bcl6 protects senescent cells from accumulating ADAR1-induced DNA damage.
• This study reveals a novel function of Bcl6 in maintaining genome stability in senescent cells.