RNA-dependent RNA polymerases in RNA silencing

2011 ◽  
Vol 392 (4) ◽  
Author(s):  
Yoshiko Maida ◽  
Kenkichi Masutomi
Keyword(s):  
Small Rnas ◽  
Rna Silencing ◽  
Rna Polymerases ◽  
Telomerase Reverse Transcriptase ◽  
Structural Homology ◽  
Small Interfering Rnas ◽  
Human Telomerase Reverse Transcriptase ◽  
Human Telomerase ◽  
Traditional Approaches

Abstract RNA-dependent RNA polymerases (RdRPs) synthesize double-stranded RNAs that are processed into small RNAs and mediate gene silencing. Viral RdRPs and cellular RdRPs show little structural homology to each other. Cellular RdRPs play key roles in RNA silencing by producing complementary strands for target RNAs via Dicer-dependent and -independent mechanisms. Although the existence of a functional mammalian homolog of RdRP has long been predicted, traditional approaches to identify such enzymes were unsuccessful. Recently, human telomerase reverse transcriptase, a polymerase closely related to viral RdRPs, has been shown to function as an RdRP and contributes to RNA silencing in vivo. These findings suggest that endogenous small interfering RNAs are produced by several mechanisms in eukaryotes.

ESTABLISHMENT OF AN IN VIVO MENINGIOMA MODEL WITH HUMAN TELOMERASE REVERSE TRANSCRIPTASE

Neurosurgery ◽  
2007 ◽  
Vol 60 (4) ◽  
pp. 750-760 ◽  
Author(s):  
Theresa G. Cargioli ◽  
Hasan C. Ugur ◽  
Naren Ramakrishna ◽  
Jennifer Chan ◽  
Peter M. Black ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Telomerase Reverse Transcriptase ◽  
Human Telomerase Reverse Transcriptase ◽  
Human Telomerase

scholarly journals Functional specialization of monocot DCL3 and DCL5 proteins through the evolution of the PAZ domain

2021 ◽  
Author(s):  
Shirui Chen ◽  
Wei Liu ◽  
Masahiro Naganuma ◽  
Yukihide Tomari ◽  
Hiro-oki Iwakawa
Keyword(s):  
Small Rnas ◽  
Rna Silencing ◽  
Functional Differentiation ◽  
Small Interfering Rnas ◽  
Double Stranded Rna ◽  
Secondary Sirnas ◽  
Fixed End ◽  
Paz Domain ◽  
Reproductive Processes

Monocot DICER-LIKE3 (DCL3) and DCL5 produce distinct 24-nt heterochromatic small interfering RNAs (hc-siRNAs) and phased secondary siRNAs (phasiRNAs). The former small RNAs are linked to plant heterochromatin, and the latter to reproductive processes. It is assumed that these DCLs evolved from an ancient "eudicot-type" DCL3 ancestor, which may have produced both types of siRNAs. However, how functional differentiation was achieved after gene duplication remains elusive. Here, we find that monocot DCL3 and DCL5 exhibit biochemically distinct preferences for 3′ overhangs and 5′ phosphates, consistent with the structural properties of their in vivo double-stranded RNA substrates. Importantly, these distinct substrate specificities are determined by the PAZ domains of DCL3 and DCL5 which have accumulated mutations during the course of evolution. These data explain the mechanism by which these DCLs cleave their cognate substrates from a fixed end, ensuring the production of functional siRNAs. Our study also indicates how plants have diversified and optimized RNA silencing mechanisms during evolution.

scholarly journals Identification of human TERT elements necessary for telomerase recruitment to telomeres

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Jens C Schmidt ◽  
Andrew B Dalby ◽  
Thomas R Cech
Keyword(s):  
Dna Sequences ◽  
Repetitive Dna Sequences ◽  
Telomerase Reverse Transcriptase ◽  
Human Chromosomes ◽  
Human Telomerase Reverse Transcriptase ◽  
Interaction Interface ◽  
Ob Fold ◽  
Human Telomerase

Human chromosomes terminate in telomeres, repetitive DNA sequences bound by the shelterin complex. Shelterin protects chromosome ends, prevents recognition by the DNA damage machinery, and recruits telomerase. A patch of amino acids, termed the TEL-patch, on the OB-fold domain of the shelterin component TPP1 is essential to recruit telomerase to telomeres. In contrast, the site on telomerase that interacts with the TPP1 OB-fold is not well defined. In this study, we identify separation-of-function mutations in the TEN-domain of human telomerase reverse transcriptase (hTERT) that disrupt the interaction of telomerase with TPP1 in vivo and in vitro but have very little effect on the catalytic activity of telomerase. Suppression of a TEN-domain mutation with a compensatory charge-swap mutation in the TEL-patch indicates that their association is direct. Our findings define the interaction interface required for telomerase recruitment to telomeres, an important step towards developing modulators of this interaction as therapeutics for human disease.

Targeting human telomerase reverse transcriptase with recombinant lentivector is highly effective to stimulate antitumor CD8 T-cell immunity in vivo

Blood ◽  
2010 ◽  
Vol 115 (15) ◽  
pp. 3025-3032 ◽  
Author(s):  
Olivier Adotévi ◽  
Karine Mollier ◽  
Christine Neuveut ◽  
Magalie Dosset ◽  
Patrice Ravel ◽  
...  
Keyword(s):  
T Cell ◽  
Reverse Transcriptase ◽  
Cd8 T Cell ◽  
T Cell Immunity ◽  
Active Immunotherapy ◽  
Telomerase Reverse Transcriptase ◽  
Human Telomerase Reverse Transcriptase ◽  
Cell Immunity ◽  
Human Telomerase

Abstract The success of active immunotherapy is based on the vaccine's ability to overcome immune tolerance through recalibrating the immune system so that it is able to recognize tumor antigens as foreign rather than self. In this study, we used a lentiviral vector system to target human telomerase reverse transcriptase (lv-hTERT), a widely expressed tumor antigen. Immunization of HLA-A*0201 transgenic HHD mice with recombinant lv-hTERT vector induces potent and diversified cytotoxic T lymphocyte responses that recognize in vitro murine tumor cells, which overexpress telomerase. Compared with peptide-based vaccinations, the lv-hTERT vector triggers better and more sustained CD8+ T-cell response against self/TERT epitope in vivo. The study found that the additional use of a heterologous boosted vaccination drastically improves self/TERT-specific CD8 responses in lv-hTERT primed mice. Both primary and long-lasting self/TERT-specific CD8+ T-cell responses induced with Iv-hTERT vector required the presence of CD4 T cells in vivo. This lv-hTERT–based active immunotherapy efficiently inhibits the growth of telomerase expressing tumors (B16/HLA-A2.1 murine melanoma) in HHD mice. These data show that targeting hTERT with lentivector is highly effective in stimulating a broad range of CD8 T-cell immunity that can be exploited for cancer immunotherapy.

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