Rev responsive element

Chapman RL, Stanley TB, Hazen R, Garvey EP. Small molecule modulators of HIV Rev/Rev response element interaction identified by random screening. Antiviral Res 2002 54 149-62. 

RRE (RNA signal) Rev responsive element 234nt segment of env in HIV-1 Exportin 1/Rev... 

Genes, env DNA sequences that form the coding region for the viral envelope (env) proteins in retroviruses. The env genes contain a cis-acting RNA target sequence for the rev protein (= gene products, rev), termed the rev-responsive element (RRE). [NIH]... 

Fig. 1.50. The function of the Rev protein in the processing of the transcripts of the Human Immunodeficincy Virns (HIV). The Rev protein is a regulatory protein reqnired for the processing of the primary transcripts of HIV. In the early stadium of viral replication, before Rev protein is available, spliced mRNA of ca. 2kb are transported to the cytosol. The spliced mRNAs are created by multiple splicing events of the primary transcript and encode the regnlatory proteins Tat, Rev and Net Once a critical level of Rev protein is formed, nnspliced (9kb) or only singly spliced (4kb) forms of the viral mRNA appear in the cytosol. These encode for strnctnral proteins and reverse transcriptase. The Rev protein binds to a particular sequence of the viral RNA, the Rev responsive element (RRE). The binding of Rev to the RRE enables the transport of unspliced viral transcript into cytosol.

Fig. 1.51. Sequence and presumed secondary structure of the Rev responsive element" of HIV RNA. The framed region is postnlated to be the binding site of the Rev protein based on mntation studies. After Heaphy et al., 1991.

Heaphy, S., Finch, IT., Gait, M.J., Karn, J. and Singh, M. Human Immunodefidency virus type-1 regulator of virion expression, rev, forms nucleoprotein filaments after binding to a purine-rich bubble located within the rev responsive element (1991) Proc. Natl. Acad. Sd. U.S.A. 88,... 

Huang, J. and Liang, T.J. (1993) A novel hepatitis B virus (HBV) genetic element with Rev response element-like properties that is essential for expression of HBV gene products. Mol. Cell. Biol, 13, 7476-7486. 

Park WKC, Auer M, Jaksche H, Wong CH, Rapid combinatorial synthesis of aminoglycoside antibiotic mimetics use of a polyethylene glycol-linked amine and a neamine-derived aldehyde in multiple component condensation as a strategy for the discovery of new inhibitors of the HIV RNA Rev responsive elements, J. Am. Chem. Soc., 118 10150-10155, 1996. 

Aminoglycoside binding to RNA is not limited to binding to prokaryotic 165 ribo-somal RNA. These positively charged molecules interact with the HlV-1 Rev Response Element (RRE) transcriptional activator region [17] and TAR RNA [151], interfere with intron splicing [146], and bind to hammerhead ribozymes [153]. 

The neamine-derived aldehyde 81 has been prepared and used in combinatorial synthesis of a library of neomycin B mimetic aminoglycoside antibiotics, a strategy for the discovery of new inhibitors for binding to the Rev-responsive element of HIV mRNA [55], The synthesis involves allylation of the selectively protected neamine derivative 80, followed by ozonolysis of the allylic double bond to generate the aldehyde functional group (compounds 80, 81). 

The critical point for the Rev protein is the processing of the 9S and 4S RNA. In the presence of Rev, the splicing of long mRNAs to the short 2S RNA is repressed and the unspliced mRNA forms can be transported from the nucleus to the cytosol. The Rev protein binds to a ca. 230 long RNA element, termed the Rev Responsive Element (RRE), which includes sequences on the 9S and 4S RNA. The binding of Rev to the RRE obviously allows the transport of the unspliced or partially spliced RNA into the cytosol. 

Fig. 7.4 The HIV-1 lentiviral-based vector contains the 5 long terminal repeat (5 -LTR), transactivation response region (TAR), packaging sequence (0), primer binding site (pbs), splice donor (SD) and acceptor (SA) sites, Rev response element (RRE), the 3 long terminal repeat (3 -LTR) and the polypurine tract (ppt) from HIV-1. It contains a cassette with the tat cDNA placed under the LacS-witch II inducible mammalian expression system...

Studies with HIV mutants showed that transport of unspllced 9-kb and singly spliced 4-kb viral mRNAs from the nucleus to the cytoplasm requires the virus-encoded Rev protein. Subsequent biochemical experiments demonstrated that Rev binds to a specific Rev-response element (RRE) present In HIV RNA. In cells infected with HIV mutants lacking the RRE, unspllced and singly spliced viral mRNAs remain in the nucleus, demonstrating that the RRE is required for Rev-mediated stimulation of transport. Rev contains a leucine-rich NES that Interacts with exportin 1 complexed with Ran GTP. As a result. Rev exports unspllced and singly spliced HIV mRNAs through interactions with exportin I and the nuclear pore complex. 

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