Chapter 46 : Reverse Transcription of Retroviruses and LTR Retrotransposons

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The conversion, well over a billion years ago, of the RNA world into the modern configuration, in which genetic information is maintained primarily in DNA, required reverse transcriptases (RTs), enzymes that were able to copy genetic information from RNA into DNA, a process called reverse transcription. With minor (but important) exceptions, for example telomerases, normal cellular processes no longer require reverse transcription, which is now primarily employed in the replication of hepadnaviruses, retroviruses, and retrotransposons. This chapter will cover the process of reverse transcription, and the RTs that are involved in the replication of retroviruses and the related long terminal repeat (LTR) retrotransposons, which have lifestyles that are similar to a retrovirus that has either lost, or never acquired, the ability to be transmitted horizontally from one cell to another. The RTs of, and reverse transcription by, non-LTR retrotransposons will be considered in the chapters that describe these elements (49–55). A substantial fraction of the work that has been done on reverse transcription and RT has focused on human immunodeficiency virus type 1 (HIV-1); this is entirely appropriate given the extent of the HIV epidemic and the fact that HIV-1 RT is the target of two important classes of anti-HIV drugs. Thus, a substantial portion of this review will describe data and insights obtained in experiments that were done with HIV-1 and HIV-1 RT. However, there are some important differences in the RTs, and the process of reverse transcription, among the different retroviruses and LTR retrotransposons; these differences will also be considered, at least briefly. The literature on RT and reverse transcription is both vast and complex. Any review, including this one, can present no more than a superficial overview of what is known. Much that is important has been omitted, some intentionally, some inadvertently; for these omissions, the author apologizes. For those who are interested, a number of helpful reviews have already been published, most of which are focused on retroviral RTs ( ).

Citation: Hughes S. 2015. Reverse Transcription of Retroviruses and LTR Retrotransposons, p 1051-1077. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0027-2014
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Image of Figure 1
Figure 1

Reverse transcription of the genome of HIV-1. This figure shows, in cartoon form, the steps that are involved in the conversion of the ssRNA genome found in virions into dsDNA. In the figure, RNA is shown in green and DNA in purple. For simplicity, the 5′ cap and the poly(A) tail, which are present on the viral genomic RNA, have been omitted. The various sequence elements in the viral genome, including the genes, are not drawn to scale. The tRNA primer (green arrow on the left) is base paired to the primer-binding site (PBS). RT has initiated minus-strand DNA synthesis from the tRNA primer, and has copied the U5 and R sequences at the 5′ end of the genome. This creates an RNA/DNA duplex, which allows RNase H to degrade the RNA that has been copied (dotted green line). The minus-strand DNA (see text) has been transferred, using the R sequence found at both ends of the viral RNA, to the 3′ end of the viral RNA, and minus-strand DNA synthesis can resume. The HIV-1 genome has two purine-rich sequences (polypurine tracts, or PPTs, one immediately adjacent to U3; the other, the central PPT [cPPT] is in the gene). The two PPTs are relatively resistant to RNase H and they serve as primers for plus-strand DNA synthesis . Once plus-strand DNA synthesis has been initiated, RNase H removes the PPT from the plus-strand DNAs . The plus-strand that is initiated in U3 is extended until the first 18 bases to the tRNA primer are copied (see text); RNase H then removes the tRNA primer . It appears that the entire PPT primers are removed by RNase H; however, RNase H leaves a single riboA on the 5′ end of the minus-strand . Removing the tRNA primer sets the stage for the second-strand transfer . Both the plus- and minus-strand DNAs are then elongated. The plus-strand that was initiated at the U3 junction (on the left in the figure) displaces a segment of the plus-strand that was initiated from the cPPT, creating a small flap, called the central flap (cFLAP).

Citation: Hughes S. 2015. Reverse Transcription of Retroviruses and LTR Retrotransposons, p 1051-1077. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0027-2014
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Image of Figure 2
Figure 2

HIV-1 RT in a complex with dsDNA and an incoming dNTP. RT is shown as a ribbon diagram; the DNA and the incoming dNTP are shown as space filling models. The p51 subunit (at the bottom) is shown in gray. The RNase H domain is shown in pink, and the four subdomains to the polymerase domain are shown in different colors: fingers, blue; thumb, green; palm, red; and connection, yellow. The DNA template strand (the strand that is being copied) is dark red and the primer strand (the strand that is being extended) is purple. The incoming dNTP is light blue.

Citation: Hughes S. 2015. Reverse Transcription of Retroviruses and LTR Retrotransposons, p 1051-1077. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0027-2014
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Image of Figure 3
Figure 3

Movement of HIV-1 RT during polymerization. The colors used for the various subunits, domains, and subdomains of RT, and for the two DNA strands, are as in Fig. 2 . The p51 subunit is gray. The RNase H domain is shown in pink, and the four subdomains to the polymerase domain are as follows: fingers, blue; thumb, green; palm, red; and connection, yellow. The DNA template is dark red and the primer strand is purple. The incoming dNTP is light blue. The structural changes in RT can be correlated with specific steps in the binding of the substrates and the incorporation of the incoming dNTP. In unliganded RT, the fingers and thumb are closed (A). Before the dsDNA (or other nucleic acid substrate) can be bound, the thumb must move (A → B); this allows the dsDNA to be bound (B). This sets the stage for the binding of the incoming dNTP. When the incoming dNTP binds, the fingers close, which allows the dNTP to be incorporated, with the release of pyrophosphate (PPi). The incorporation of the dNTP temporarily leaves the end of the primer stand in the N or nucleoside triphosphate-binding site (see text). Translocation moves the nucleic acid by 1 bp, which allows the next dNTP to be bound and incorporated.

Citation: Hughes S. 2015. Reverse Transcription of Retroviruses and LTR Retrotransposons, p 1051-1077. In Craig N, Chandler M, Gellert M, Lambowitz A, Rice P, Sandmeyer S (ed), Mobile DNA III. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MDNA3-0027-2014
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