Elucidating the role of adenosine-to-inosine RNA editing in B2 sine RNAs during cellular stress

Abstract

Although only approximately 2% of the mammalian genome encodes proteins, much of the remaining genome is transcribed into non-coding RNAs with important regulatory functions. Among these, murine B2 Short Interspersed Nuclear Element (SINE) RNAs are rapidly induced during cellular stress and repress RNA polymerase II activity; however, the mechanisms governing their regulation and the contribution of adenosine-to-inosine (A-to-I) RNA editing remain poorly understood. In this thesis, multiple experimental approaches were used to investigate the role of ADAR proteins in regulating B2 SINE RNAs during cellular stress. Stress-induced B2 RNA accumulation was associated with dynamic changes in RNA processing and distinct A-to-I editing profiles in both full-length and processed B2 RNA populations. Functional studies demonstrated that ADAR1 regulates B2 RNAs through both editing-dependent and editing-independent mechanisms, promoting B2 RNA processing while A-to-I editing altered the susceptibility of B2 RNAs to protein-mediated processing. Furthermore, coordinated regulation of sense and antisense B2 transcripts suggests that interactions between complementary B2 RNAs may contribute to their regulation during cellular stress. Collectively, these findings establish ADAR1 as a key regulator of B2 SINE RNA biology and provide new insights into the interplay between RNA editing, RNA processing, and B2 SINE RNA regulation during cellular stress. These findings provide a foundation for future studies investigating the contribution of ADAR-mediated B2 RNA regulation to cellular stress adaptation and disease.