RNA deadenylation complexes in development and diseases

Abstract

RNA deadenylation, the process of shortening of the 3’ poly(A) tail of an RNA molecule, is one of the key steps of post-transcriptional regulation of gene expression in eukaryotic cells. PAN2/3 and CCR4-NOT (CNOT) are the two dominant RNA deadenylation complexes, which play central roles in mediating mRNA decay and translation. While degradation is the final fate of virtually all RNAs in their life cycles, selection of RNA targets as well as control of the rate and timing of RNA decay, in coordination with other molecular pathways, including translation, can be modulated in certain contexts. Such regulation influences cell growth, proliferation, and differentiation at the cellular level; and contributes to establish polarity and regulate signaling at the tissue level. Dysregulation of deadenylation processes have also been implicated in human diseases ranging from cardiac diseases and neurodevelopmental disorders to cancers. In this review, we will discuss mechanisms of gene expression control mediated by the RNA deadenylation complexes and highlight relevant evidence supporting the emerging roles of RNA deadenylation and its regulatory proteins during development and in diseases. A systemic understanding of these mechanisms will be a critical foundation for development of effective strategies to therapeutically target them.

Pathogenicity analysis and splicing rescue of a classical splice site variant (c.1343+1G>T) of CNOT1 gene associated with neurodevelopmental disorders

“…Also, it was found that the variant‐specific Drosophila model showed learning and memory deficits in a courtship suppression behavior after CNOT1 knockdown. Interestingly, the mutant could be partially rescued by introducing human wild‐type CNOT1 , which further supports our hypothesis that CNOT1 damage causes neurodevelopment delay (Liu et al, 2023; Vissers et al, 2020).…”

“…Interestingly, the mutant could be partially rescued by introducing human wild-type CNOT1, which further supports our hypothesis that CNOT1 damage causes neurodevelopment delay (Liu et al, 2023;Vissers et al, 2020).…”

“…CNOT1 enables binding a motif of tristetraprolin (TTP), a zinc finger protein 36 homolog, directly, then TTP binds the adenylate uridylate-rich elements on mRNA to promote deadenylation (Fabian et al, 2013). RNA deadenylation has been reported to be one of the critical steps in the post-transcriptional regulation of gene expression in eukaryotic cells, and its dysregulation has been associated with human diseases ranging from heart disease and neurodevelopmental disorders to cancer (Liu et al, 2023). Vissers et al strongly inferred that variants in CNOT1 are related to neurodevelopmental disorders based on the analysis of 39 individuals from 37 families with heterozygous de novo variants (Vissers et al, 2020).…”