Chapter 54 : An Unexplored Diversity of Reverse Transcriptases in Bacteria

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Reverse transcriptase (RT) is generally considered a eukaryotic enzyme because it is prevalent in eukaryotes and was first characterized from eukaryotic sources. Discovered in 1970 in the Rous Sarcoma and murine leukemia viruses ( ), RT has since been studied for its central role in the replication of many eukaryotic genetic elements including retroviruses (e.g., HIV-1), pararetroviruses, hepadnaviruses, long terminal repeat (LTR), and non-LTR retroelements, Penelope-like elements, and telomerase ( ). Over the years, the accumulated studies of RT have painted a picture in which the enzyme functions primarily as the replicative enzyme of selfish DNAs (viruses, retrotransposons), while occasionally becoming domesticated to perform useful cellular functions. These functions include the maintenance of chromosomal ends (telomerase, Het-A elements) ( ) and contributions to genomic change (both beneficial and deleterious) through pseudogene formation or other retroprocessing events ( ).

Citation: Zimmerly S, Wu L. 2015. An Unexplored Diversity of Reverse Transcriptases in Bacteria, p 1253-1269. 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.MDNA3-0058-2014
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Image of Figure 1
Figure 1

Group II introns. (A) The genomic structure of a group II intron consists of sequence for an RNA structure (∼500 to 800 bp; red boxes) and an ORF for an intron-encoded protein (green). The protein contains a reverse transcriptase (RT) domain with motifs 0 to 7, an X/thumb domain, a DNA-binding domain (D), and sometimes, an endonuclease domain (En). The intron is flanked by exons E1 and E2 (blue). The structure is drawn to scale for the Ll.LtrB intron of . (B) After transcription of the intron, the intron-encoded protein is translated from unspliced transcript and binds to the RNA structure to facilitate a two-step splicing reaction, yielding spliced exons and an RNP consisting of the RT and intron lariat RNA. (C) The RNP inserts intron sequence into new genomic targets. To do this, the RNP binds to the double-stranded DNA target, the intron lariat reverse splices into the top strand, and the En domain cleaves the bottom strand to produce a primer that is reverse transcribed by the RT. Cellular repair activities convert the insertion product to dsDNA.

Citation: Zimmerly S, Wu L. 2015. An Unexplored Diversity of Reverse Transcriptases in Bacteria, p 1253-1269. 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.MDNA3-0058-2014
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Figure 2

Diversity-generating retroelements (DGRs). A DGR consists of a reverse transcriptase (RT) gene with seven motifs, a target gene with a C-terminal variable region (VR), a template repeat (TR), and usually, an accessory variability determinant gene () (drawn to scale for the phage DGR [ ]). The RT’s thumb motif is not defined in sequence but presumably would be present downstream of motif 7. For the mutagenic homing reaction, the RT reverse transcribes the TR transcript and the resulting cDNA is integrated into the target gene to replace the previous VR sequence. During this process, each A in the TR sequence is mutagenized to any nucleotide, producing directed randomization of the VR sequence in the target gene.

Citation: Zimmerly S, Wu L. 2015. An Unexplored Diversity of Reverse Transcriptases in Bacteria, p 1253-1269. 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.MDNA3-0058-2014
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Figure 3

Retrons. A retron consists of an inverted repeat sequence corresponding to msRNA and msDNA genes, and a reverse transcriptase (RT) with seven conserved motifs (drawn to scale for retron Ec86 [ ]). The thumb domain is presumably located directly downstream of motif 7. All three genes are transcribed in a single transcript and the RT binds to the RNA structure formed by the inverted repeat sequence. A specific G residue presents a 2′OH that acts as the primer for reverse transcription. After removal of the RNA template by cellular RNase H, the final msDNA consists of one RNA and one DNA linked by a 2′OH bond, and base paired at the 3′ ends of both.

Citation: Zimmerly S, Wu L. 2015. An Unexplored Diversity of Reverse Transcriptases in Bacteria, p 1253-1269. 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.MDNA3-0058-2014
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Figure 4

Classes of reverse transcriptases (RTs) and RT-like sequences in bacterial genomes. The figure is an update of Fig. 1 in reference . A set of 3,044 RTs were collected from GenBank and classified according to alignability of RT motif sequences, phylogenetic analyses, and the presence of additional domains. The number of members in each class is indicated in parentheses and by the area of the gray triangles. RT motifs are denoted by boxes that are either black (clearly alignable with group II introns), gray (ambiguously alignable), or white (not alignable, although an analogous structure is expected to be present). Sizeable extensions to the RTs are indicated by amino acid sizes, and are in parentheses when the motif is present in fewer than half of the examples. Protein motifs identified by either CDD of NCBI or Pfam are Cas1, trypsin, gluzincin, nitrilase, fimbrial, and primase. Biological properties associated with the different classes are indicated to the right.

Citation: Zimmerly S, Wu L. 2015. An Unexplored Diversity of Reverse Transcriptases in Bacteria, p 1253-1269. 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.MDNA3-0058-2014
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Figure 5

Amino acid alignment of reverse transcriptase (RT) motifs 0 to 7 for different classes of RTs in bacteria and eukaryotes. Three example sequences are presented for each class for motifs 0 to 7. Sequences in black lettering and bold color shading are clearly alignable with group II introns, while sequences in gray and light color shading are ambiguously alignable. Sequences not shown indicate unalignability with group II RT sequence motifs, although similar structures are likely present in the proteins. Positions with >30% identity across the entire alignment are back-shaded in colors to highlight the most conserved residues across RT classes. For comparison, the sequences of major classes of eukaryotic RTs are listed, as well as a consensus sequence for the Pfam group, RNA-dependent RNA polymerase (RdRP) 1, which among RdRPs has the greatest alignability to group II RTs. Asterisks above the alignment mark the three catalytic aspartate residues in motifs 3 and 5 and the active site lysine in motif 6. DGRs, diversity-generating retroelements; LTR, long terminal repeat; PLEs, Penelope-like elements; TERT, telomerase reverse transcriptase.

Citation: Zimmerly S, Wu L. 2015. An Unexplored Diversity of Reverse Transcriptases in Bacteria, p 1253-1269. 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.MDNA3-0058-2014
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Figure 6

AbiK and abortive infection. (A) During abortive infection by AbiK, the phage injects its DNA into a cell, but the multiplication cycle is blocked through an undefined mechanism by the AbiK protein. Although not necessarily a suicide mechanism, most cells still die and infective phages are not released. (B) The AbiK protein contains reverse transcriptase (RT) motifs 1 to 6 and 7 is essentially unalignable with group II introns. Estimates for the boundaries of the RT domain and thumb domain of the polymerase are indicated with dotted lines. In addition, the proteins contain a short N-terminal extension and a ∼840 bp C-terminal extension (drawn to scale for AbiK of [ ]). (C) Purified AbiK protein has a terminal transferase activity, with the synthesized DNA becoming covalently linked to the AbiK protein. In the “label” reaction with low concentrations of [α-P]TTP, AbiK produce a short poly T DNA that is covalently linked to the AbiK protein. In the “chase” reaction, high concentrations of dNTPs cause polymerization of hundreds of nucleotides of heterogeneous sequence.

Citation: Zimmerly S, Wu L. 2015. An Unexplored Diversity of Reverse Transcriptases in Bacteria, p 1253-1269. 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.MDNA3-0058-2014
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Figure 7

The element. (A) The RVT ORF contains reverse transcriptase (RT) motifs 1 to 6, while motif 7 and thumb domains are unalignable with group II RTs but are presumably present in the polymerase structure. Estimates for the boundaries of the RT domain and thumb domain of the polymerase are noted with dotted lines. The large N-terminal and C-terminal extensions have no detectable protein motifs (drawn to scale for the RVT [ ]). (B) Purified RVT protein has terminal transferase activity that requires an RNA or DNA primer and has a preference for nucleoside triphosphates (NTPs) over deoxynucleoside triphosphates (dNTPs). When purified RVT protein is incubated with [α-P]dCTP, a short sequence is synthesized, which is extended by either NTPs or dNTPs in a chase reaction.

Citation: Zimmerly S, Wu L. 2015. An Unexplored Diversity of Reverse Transcriptases in Bacteria, p 1253-1269. 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.MDNA3-0058-2014
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