Novel functional role of CA repeats and hnRNP L in RNA stability

Abstract

CA dinucleotide repeat sequences are very common in the human genome. We have recently demonstrated that the polymorphic CA repeats in intron 13 of the human endothelial nitric oxide synthase (eNOS) gene function as an unusual, lengthdependent splicing enhancer. The CA repeat enhancer requires for its activity specific binding of hnRNP L. Here we show that in the absence of bound hnRNP L, the pre-mRNA is cleaved directly upstream of the CA repeats. The addition of recombinant hnRNP L restores RNA stability. CA repeats are both necessary and sufficient for this specific cleavage in the 5 adjacent RNA sequence. We conclude that-in addition to its role as a splicing activator-hnRNP L can act in vitro as a sequence-specific RNA protection factor. Based on the wide abundance of CA repetitive sequences in the human genome, this may represent a novel, generally important role of this abundant hnRNP protein.

The role of the 3' untranslated region in post-transcriptional regulation of protein expression in mammalian cells.

“…66,67,79,80 has been described as the main CARE interacting partner that ensures the effectiveness of stabilization. 102 The exact mechanisms of stabilization or destabilization of related mRNAs are still unclear but it is proposed that hnRNP L binding alters susceptibility of mRNAs to degradation by endoor exo-nucleases. 103 In the case of VEGF, two adjacent regulatory sequences were found within the 3' UTR, the CARE target for stabilization through hnRNP L and a GAIT element (IFNγ-activated inhibitor of translation), a target for the GAIT complex that silences inflammatory gene expression in particular.…”

A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample

“…Although single-nucleotide polymorphisms (SNPs) are markers of great utility in genetic studies, different alleles of a VNTR represent a very large physical and chemical change to a stretch of DNA sequence. They can act variously as (i) functional elements binding transcription factors and other proteins that inhibit or promote expression (18,19); (ii) motif elements affecting the efficiency of mRNA splicing (20); (iii) elements having physical effects, such as varying the spacing between functional motifs or altering the structure and melting properties of DNA in their proximity. For these reasons we regard VNTRs as very good a priori functional candidates.…”

Separate cis-trans Pathways Post-transcriptionally Regulate Murine CD154 (CD40 Ligand) Expression

“…This is particularly important due to the presence of other 3Ј-UTR elements (polycytidines, CA repeats) in this region that are associated with post-transcriptional gene regulation (17)(18)(19)(20)(21). The conserved murine CD154 3Ј-UTR has advantages for this analysis, given the condensed (180 nt) nature of the CU-and CA-rich regions (Fig.…”