Adaptive transcription-splicing resynchronization upon losing an essential splicing factor

Essential genes form the core of a genome and are therefore thought to be indispensable for cellular viability. However, recent findings have challenged this notion in that cells may survive in the absence of some essential genes provided that relevant genetic modifiers are in existence. We therefore hypothesized that the loss of an essential gene may not always be fatefully detrimental; instead, it may pave the way towards genome evolution. We experimentally tested this hypothesis in the context of pre-messenger RNA splicing by evolving yeast cells harbouring a permanent loss of the essential splicing factor Prp28 in the presence of a genetic modifier. Here, we show that cellular fitness can be restored by compensatory mutations that alter either the splicing machinery per se or the Spt-Ada-Gcn5 acetyltransferase transcription co-activator complex in the cells with no Prp28. Biochemical and genetic analysis revealed that slowing down transcription compensates for splicing deficiency, which in turn boosts cellular fitness. In addition, we found that inefficient splicing also conversely decreases nascent RNA production. Taken together, our data suggest that transcription-splicing synchronization contributes to robustness in the gene-expression pathway and argue that the intrinsic interconnectivity within a biological system can be exploited for compensatory evolution and system re-optimization.