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Item Profiling neural editomes reveals a molecular mechanism to regulate RNA editing during development(Cold Spring Harbor Laboratory Press, 2021-01) Rajendren, Suba; Dhakal, Alfa; Vadlamani, Pranathi; Townsend, Jack; Deffit, Sarah N.; Hundley, Heather A.; Biology, School of ScienceAdenosine (A) to inosine (I) RNA editing contributes to transcript diversity and modulates gene expression in a dynamic, cell type-specific manner. During mammalian brain development, editing of specific adenosines increases, whereas the expression of A-to-I editing enzymes remains unchanged, suggesting molecular mechanisms that mediate spatiotemporal regulation of RNA editing exist. Herein, by using a combination of biochemical and genomic approaches, we uncover a molecular mechanism that regulates RNA editing in a neural- and development-specific manner. Comparing editomes during development led to the identification of neural transcripts that were edited only in one life stage. The stage-specific editing is largely regulated by differential gene expression during neural development. Proper expression of nearly one-third of the neurodevelopmentally regulated genes is dependent on adr-2, the sole A-to-I editing enzyme in C. elegans However, we also identified a subset of neural transcripts that are edited and expressed throughout development. Despite a neural-specific down-regulation of adr-2 during development, the majority of these sites show increased editing in adult neural cells. Biochemical data suggest that ADR-1, a deaminase-deficient member of the adenosine deaminase acting on RNA (ADAR) family, is competing with ADR-2 for binding to specific transcripts early in development. Our data suggest a model in which during neural development, ADR-2 levels overcome ADR-1 repression, resulting in increased ADR-2 binding and editing of specific transcripts. Together, our findings reveal tissue- and development-specific regulation of RNA editing and identify a molecular mechanism that regulates ADAR substrate recognition and editing efficiency.Item A protein-protein interaction underlies the molecular basis for substrate recognition by an adenosine-to-inosine RNA-editing enzyme(Oxford University Press, 2018-10-12) Rajendren, Suba; Manning, Aidan C.; Al-Awadi, Haider; Yamada, Kentaro; Takagi, Yuichiro; Hundley, Heather A.; Biochemistry and Molecular Biology, School of MedicineAdenosine deaminases that act on RNA (ADARs) convert adenosine to inosine within double-stranded regions of RNA, resulting in increased transcriptomic diversity, as well as protection of cellular double-stranded RNA (dsRNA) from silencing and improper immune activation. The presence of dsRNA-binding domains (dsRBDs) in all ADARs suggests these domains are important for substrate recognition; however, the role of dsRBDs in vivo remains largely unknown. Herein, our studies indicate the Caenorhabditis elegans ADAR enzyme, ADR-2, has low affinity for dsRNA, but interacts with ADR-1, an editing-deficient member of the ADAR family, which has a 100-fold higher affinity for dsRNA. ADR-1 uses one dsRBD to physically interact with ADR-2 and a second dsRBD to bind to dsRNAs, thereby tethering ADR-2 to substrates. ADR-2 interacts with >1200 transcripts in vivo, and ADR-1 is required for 80% of these interactions. Our results identify a novel mode of substrate recognition for ADAR enzymes and indicate that protein-protein interactions can guide substrate recognition for RNA editors.Item To protect and modify double-stranded RNA – the critical roles of ADARs in development, immunity and oncogenesis(Taylor & Francis, 2021) Erdmann, Emily A.; Mahapatra, Ananya; Mukherjee, Priyanka; Yang, Boyoon; Hundley, Heather A.; Biology, School of ScienceAdenosine deaminases that act on RNA (ADARs) are present in all animals and function to both bind double-stranded RNA (dsRNA) and catalyze the deamination of adenosine (A) to inosine (I). As inosine is a biological mimic of guanosine, deamination by ADARs changes the genetic information in the RNA sequence and is commonly referred to as RNA editing. Millions of A-to-I editing events have been reported for metazoan transcriptomes, indicating that RNA editing is a widespread mechanism used to generate molecular and phenotypic diversity. Loss of ADARs results in lethality in mice and behavioral phenotypes in worm and fly model systems. Furthermore, alterations in RNA editing occur in over 35 human pathologies, including several neurological disorders, metabolic diseases and cancers. In this review, a basic introduction to ADAR structure and target recognition will be provided before summarizing how ADARs affect the fate of cellular RNAs and how researchers are using this knowledge to engineer ADARs for personalized medicine. In addition, we will highlight the important roles of ADARs and RNA editing in innate immunity and cancer biology.