Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.26.4 (
RNase H
)
2,751
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
This article reviews the authors' investigation of the enzyme
RNase H
(EC 3.1.4.34.) in human leukemic cells and presents the accumulated available data, based on which this enzyme is proposed to serve as a new biological parameter in the study of progression of human leukemias. The introduction gives a brief account of the occurrence, characterization and possible biological role of
RNase H
in cells and in retroviruses. The results reviewed briefly concern: (1) the development of a new convenient, economic and reliable assay for normal and leukemic blood mononuclear cell
RNase H
, which is capable of resolving subtle activity differences between samples; (2) the differentiation of
RNase H
levels between normal and leukemic cells; (3) the correlation of
RNase H
levels from different leukemia types with the severity of the disease; (4) the correlation of
RNase H
levels in leukemic cells with clonogenic stages in the clonal differentiation pathway; (5) the predictive potential of a
RNase H
activity-based parameter (phi) in assessing progression in acute myelocytic leukemia and (6) the possibility of differentiation of the
RNase H
levels between normal and leukemic cells via regulation of the enzyme activity at the level of antagonistic phosphorylations mediated by
cAMP
and calmodulin.
...
PMID:RNase H of human leukemic cells: a new biological parameter in the study of human leukemias (review). 217 71
Fully phosphorothioate antisense oligonucleotides (ASOs) with locked nucleic acids (LNAs) improve target affinity,
RNase H
activation and stability. LNA modified ASOs can cause hepatotoxicity, and this risk is currently not fully understood. In vitro cytotoxicity screens have not been reliable predictors of hepatic toxicity in non-clinical testing; however, mice are considered to be a sensitive test species. To better understand the relationship between nucleotide sequence and hepatotoxicity, a structure-toxicity analysis was performed using results from 2 week repeated-dose-tolerability studies in mice administered LNA-modified ASOs. ASOs targeting human Apolipoprotien C3 (Apoc3), CREB (
cAMP
Response Element Binding Protein) Regulated Transcription Coactivator 2 (Crtc2) or Glucocorticoid Receptor (GR, NR3C1) were classified based upon the presence or absence of hepatotoxicity in mice. From these data, a random-decision forest-classification model generated from nucleotide sequence descriptors identified two trinucleotide motifs (TCC and TGC) that were present only in hepatotoxic sequences. We found that motif containing sequences were more likely to bind to hepatocellular proteins in vitro and increased P53 and NRF2 stress pathway activity in vivo. These results suggest in silico approaches can be utilized to establish structure-toxicity relationships of LNA-modified ASOs and decrease the likelihood of hepatotoxicity in preclinical testing.
...
PMID:Sequence motifs associated with hepatotoxicity of locked nucleic acid--modified antisense oligonucleotides. 2455 Jan 63
