Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development

Abstract

RNA editing and splicing are the two major processes that dynamically regulate human transcriptome diversity. Despite growing evidence of crosstalk between RNA editing enzymes (mainly ADAR1) and splicing machineries, detailed mechanistic explanations and their biological importance in diseases, such as cancer are still lacking. Herein, we identify approximately a hundred high-confidence splicing events altered by ADAR1 and/or ADAR2, and ADAR1 or ADAR2 protein can regulate cassette exons in both directions. We unravel a binding tendency of ADARs to dsRNAs that involves GA-rich sequences for editing and splicing regulation. ADAR1 edits an intronic splicing silencer, leading to recruitment of SRSF7 and repression of exon inclusion. We also present a mechanism through which ADAR2 binds to dsRNA formed between GA-rich sequences and polypyrimidine (Py)-tract and precludes access of U2AF65 to 3′ splice site. Furthermore, we find these ADARs-regulated splicing changes per se influence tumorigenesis, not merely byproducts of ADARs editing and binding.

Intrinsic Regulatory Role of RNA Structural Arrangement in Alternative Splicing Control

“…In consequence, these exons were expected to be looped out while upstream 5′ss and downstream 3′ss were brought together and preferentially selected [ 149 ]. Accordingly, RNA long-distance interactions and subsequent looping out of alternative exons may be mediated by ADAR, independently on its editing activity, as it was proposed for regulation of alternative exon 9 of pre-mRNA of coiled-coil domain containing 15 ( CCDC15 ) [ 140 ] ( Figure 3 b). Coordination of AS by long-range interactions was also confirmed in multiple Drosophila melanogaster pre-mRNAs [ 185 ].…”

“…Its initially discovered role was assigned to translation regulation as inosine is interpreted as a guanosine by the ribosome, whereas the editing itself was believed to occur mostly post-transcriptionally [ 136 ]. Further extensive analyses confirmed cotranscriptional editing and tightly coupled its functional importance with splicing by describing the interplay between ADAR itself, ADAR-driven disturbance of RNA structure or a sequence motif of cis -acting sites and splicing machinery or auxiliary factors [ 137 , 138 , 139 , 140 ]. Given that endogenous editing efficiency is transcript-specific and occurs in a variable manner for each transcript copy, it suggests a complex and multilayered regulation of ADAR activity.…”

ADAR2 deaminase activity promotes Th17 effector function and protects against intestine inflammation

“…For instance, ADAR2 binding to Hif1a splicing junctions could directly limit the accessibility of the RNA transcript to the splicing machinery. ADAR2 may also recruit and/or cooperate with other negative regulators of splicing to form large protein complexes to interfere with Hif1a processing indirectly (Tang et al, 2020). Future studies will be needed to evaluate these possibilities.…”

Clinical Relevance of RNA Editing to Early Detection of Cancer in Human

“…RNA editing could be used to unravel dormant cancer stem cells that often escape chemotherapies [2,3,5]. In this way the RNA editing could be used that target therapeutic resistance and tumor relapse, RNA, a short-intermediate of DNA, is responsible for protein production in cells [1,2].…”