The Goldilocks state of transcriptional readthrough for chimeric splicing

Proper transcription termination coupled to pre-mRNA cleavage and polyadenylation is an important step in gene expression as it generates the 3'UTR of mRNAs and defines transcription units. Defective termination (transcriptional readthrough) can suppress transcription of downstream genes by transcriptional interference but can also promote the production of chimeric transcripts, which contain the exons of upstream genes spliced to exons of downstream genes. This review will summarize current findings of chimeric splicing between exons of adjacent genes generated by transcriptional readthrough and the conditions that promote these events. Chimeric splicing can be facilitated by inactivation of factors that promote transcription termination or of specific splicing factors, particularly those involved in 3'-splice site recognition. This effect is due to the tight coupling between recognition of the terminal intron 3'-splice site and of the downstream polyadenylation sites, and its impact on transcriptional termination. Production of chimeric transcripts is also increased in cellular conditions that perturb transcription termination, such as cellular stress, treatment with the chemotherapeutic agent Imatinib or viral infections. However, not all conditions that promote transcriptional readthrough result in chimeric splicing, suggesting that the production of chimeric mRNAs requires a "Goldilocks" state of alteration of the transcriptional machinery that allows for transcriptional readthrough without a general reduction of splicing efficiency.