Transcription-coupled processes such as capping, splicing, and cleavage/polyadenylation participate in the journey from genes to proteins. Although they are traditionally thought to serve only as steps in the generation of mature mRNAs, a synthesis of available data indicates that these processes could also act as a driving force for the evolution of eukaryotic genes. A theoretical framework for how mRNA-associated processes may shape gene structure and expression has recently been proposed. Factors that promote splicing and cleavage/polyadenylation in this framework compete for access to overlapping or neighboring signals throughout the transcription cycle. These antagonistic interactions allow mechanisms for intron gain and splice site recognition as well as common trends in eukaryotic gene structure and expression to be coherently integrated. Here, I extend this framework further. Observations that largely (but not exclusively) revolve around the formation of DNA-RNA hybrid structures, called R loops, and promoter directionality are integrated. Additionally, the interplay between splicing factors and cleavage/polyadenylation factors is theorized to also affect the formation of intragenic DNA double-stranded breaks thereby contributing to intron loss. The most notable prediction in this proposition is that RNA molecules can mediate intron loss by serving as a template to repair DNA double-stranded breaks. The framework presented here leverages a vast body of empirical observations, logically extending previous suggestions, and generating verifiable predictions to further substantiate the view that the intracellular environment plays an active role in shaping the structure and the expression of eukaryotic genes.
Keywords: Cleavage and polyadenylation; DNA double-strand breaks; Intron loss; Intronization; Promoter directionality; R loops; Splicing; U1 snRNP; U1-dependent definition.
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