Protein Binding to Cis-Motifs in mRNAs Coding Sequence Is Common and Regulates Transcript Stability and the Rate of Translation

Abstract

Protein binding to the non-coding regions of mRNAs is relatively well characterized and its functionality has been described in many examples. New results obtained by high-throughput methods indicate that binding to the coding sequence (CDS) by RNA-binding proteins is also quite common, but the functions thereof are more obscure. As described in this review, CDS binding has a role in the regulation of mRNA stability, but it has also a more intriguing role in the regulation of translational efficiency. Global approaches, which suggest the significance of CDS binding along with specific examples of CDS-binding RBPs and their modes of action, are outlined here, pointing to the existence of a relatively less-known regulatory network controlling mRNA stability and translation on yet another level.

The RNA-binding landscape of HAX1 protein indicates its involvement in ribosome biogenesis and translation

“…Interestingly, K d values previously reported for HAX1 binding to 3'UTR are lower (Sarnowska et al 2007), indicating different strength of interaction and, possibly, different mode of binding for CDS and 3'UTR regions. Similar phenomenon was also observed for GLD-1 and FMRP proteins, involved in the regulation of translation (Grzybowska and Wakula 2021).…”

“…However, new high-throughput analyzes demonstrated that binding to the CDS is not as uncommon as previously thought and may have a role in the regulation of mRNA stability (Grzybowska and Wakula 2021). Interestingly, this stabilization should refer to the situation when mRNA is not actively translated, thus it is not covered and protected by ribosomes and susceptible to endonuclease attack, like in case of protein CRD-BP, which binds to c-myc mRNA, protecting it (Lemm and Ross 2002).…”

“…Analysis of genomic position of RNA targets obtained using CRAC method revealed the prevalence of coding sequence (CDS) regions, which is not typical for the regulatory RNA sequence and not consistent with the genomic position of previously characterized HAX1 binding regions (3’UTRs). However, new high-throughput analyzes demonstrated that binding to the CDS is not as uncommon as previously thought and may have a role in the regulation of mRNA stability (Grzybowska and Wakula 2021). Interestingly, this stabilization should refer to the situation when mRNA is not actively translated, thus it is not covered and protected by ribosomes and susceptible to endonuclease attack, like in case of protein CRD-BP, which binds to c-myc mRNA, protecting it (Lemm and Ross 2002).…”

The role of secondary structures in the functioning of 3′ untranslated regions of mRNA

“…[2] Secondary structures within coding sequence mainly impact the speed of transcription and splicing (including alternative splicing), though they can also influence transport and translation. [3][4][5] Secondary structures to maintain mRNA stability might be present, presumably, in all parts of the transcript. [3,4,6] 3′ UTRs include cis-elements implicated in a range of functions including: translational regulation, subcellular localization, and stability.…”

“…[3][4][5] Secondary structures to maintain mRNA stability might be present, presumably, in all parts of the transcript. [3,4,6] 3′ UTRs include cis-elements implicated in a range of functions including: translational regulation, subcellular localization, and stability. [7] In humans, the average length of 3′ UTRs is 1028 nt, [8] whereas in yeast, it is 144 nt.…”