Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.4 (RNase H)
 2,751 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antisense oligonucleotides (ASOs) are synthetic oligonucleotides that alter expression of disease-associated transcripts via Watson-Crick hybridization. ASOs that function through RNase H or the RNA-induced silencing complex (RISC) result in enzymatic degradation of target RNA. ASOs designed to sterically block access of proteins to the RNA modulate mRNA metabolism but do not typically cause degradation. Here, we rationally design steric blocking ASOs to promote mRNA reduction and characterize the terminating mechanism. Transfection of ASOs complementary to constitutive exons in STAT3 and Sod1 results in greater than 70% reduction of mRNA and protein. The ASOs promote aberrant exon skipping and generation of premature termination codon (PTC)-containing mRNAs. We inhibit the nonsense-mediated mRNA decay (NMD) pathway and show that the PTC-containing mRNAs are recognized by the UPF1 ATPase, cleaved by the SMG6 endonuclease and degraded by the XRN1 cytoplasmic exonuclease. NMD surveillance, however, does not entirely explain the mechanism of decreased STAT3 expression. In addition to exon skipping, ASO treatment causes intron retention and reduction of chromatin-associated STAT3 mRNA. The application of steric blocking ASOs to promote RNA degradation allows one to explore more nucleotide modifications than tolerated by RNase H or RISC-dependent ASOs, with the goal of improving ASO drug properties.
...
PMID:Nonsense-mediated decay as a terminating mechanism for antisense oligonucleotides. 2458 81

RNA therapeutics have received much attention in the development of anti-cancer therapies. Among them, synthetic mRNA (IVT mRNA) was investigated for cancer immunotherapy due to its abilities to express tumor associated antigens with stimulation of immune responses in dendritic cells (DCs). Despite of its great potential, several hurdles were remained such as insufficient immune stimulation and DC maturation. In this study, we aimed to present a novel IVT mRNA that can simultaneously express tumor associated antigens while suppress STAT3 proteins. Combined functions of siRNA and IVT mRNA were investigated and the hybrid structure of siRNA tailed mRNA (ChriST mRNA) was developed. We prepared the ChriST mRNA by employing polyA tail structures with RNAi sequences at the 3' end of mRNA. Complementary strands were annealed to form duplex siRNA structure to induce STAT3 gene silencing. In addition, a hybrid structure of DNA/RNA was introduced into the ChriST mRNA between polyA tail and RNAi sequences. It was expected that DNA/RNA duplex would be readily cleaved by RNase H in the intracellular environment. After the cleavage, ChriST mRNA was fully functionalized in cells and exhibited enhanced tumor specific DC maturation.
 ...
PMID:Combined hybrid structure of siRNA tailed IVT mRNA (ChriST mRNA) for enhancing DC maturation and subsequent anticancer T cell immunity. 3279 Oct 78