Sequence Determinants for Nuclear Retention and Cytoplasmic Export of mRNAs and lncRNAs

Eukaryotes are divided into two major compartments: the nucleus where RNA is synthesized and processed, and the cytoplasm, where mRNA is translated into proteins. Although many different RNAs are made, only a subset is allowed access to the cytoplasm, primarily RNAs involved in protein synthesis (mRNA, tRNA, and rRNA). In contrast, nuclear retained transcripts are mostly long non-coding RNAs (lncRNAs) whose role in cell physiology has been a source of much investigation in the past few years. In addition, it is likely that many non-functional RNAs, which arise by spurious transcription and misprocessing of functional RNAs, are also retained in the nucleus and degraded. In this review, the main sequence features that dictate whether any particular mRNA or lncRNA is a substrate for retention in the nucleus, or export to the cytoplasm, are discussed. Although nuclear export is promoted by RNA-splicing due to the fact that the spliceosome can help recruit export factors to the mature RNA, nuclear export does not require splicing. Indeed, most stable unspliced transcripts are well exported and associate with these same export factors in a splicing-independent manner. In contrast, nuclear retention is promoted by specialized cis-elements found in certain RNAs. This new understanding of the determinants of nuclear retention and cytoplasmic export provides a deeper understanding of how information flow is regulated in eukaryotic cells. Ultimately these processes promote the evolution of complexity in eukaryotes by shaping the genomic content through constructive neutral evolution.