Nuclear RNA Sorting

Mammalian genomes are hyperactively transcribed and, paradoxically, a major part of the produced RNA is turned over soon after its synthesis. But the situation is even more bizarre. This is because individual transcription units (TUs), that generate standard functional transcripts, also give rise to a flock of shorter labile isoforms. Overall, this presents an extraordinarily chaotic situation where the expression of functional RNA, both at the genomic- and at the single TU-level, is embedded within a sea of futile transcription products. Being predominantly transcribed by RNA polymerase II, labile RNAs share common features with their functional counterparts, which motivates the basic question of the NuRS proposal: Which molecular mechanisms dictate the sorting of nuclear RNAs into stable, functional ribonucleoprotein particles vs. those destined for degradation? The major challenge of mechanistically rationalizing RNA sorting has for long been without concrete and testable hypotheses. However, recent breakthroughs by us, and others, have found that the essential ARS2 protein holds binary functions in RNA maturation and degradation. Given its cap-proximal omnipresence on nascent RNA, we hypothesize that transcript fate is governed by the competitive interaction of ARS2 with productive and destructive factors. Through a delineation of the responsible protein complexes and domains, we will dissect the underlying molecular logic, both at steady state and in the dynamic context of stem cell differentiation. This includes exploring our provocative finding that the domain of ARS2, interacting with RNA processing and degradation factors, can also interact with transcription factors. How these transcriptional and post-transcriptional links impinge on RNA sorting will be uncovered, which will disclose the fundamental question of how cells cope with a massive genomic output without erroneously degrading functional RNA or leaving spurious transcripts ignored.