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P Transposable Elements in and other Eukaryotic Organisms

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  • Authors: Sharmistha Majumdar*1, Donald C. Rio3
  • Editors: Mick Chandler4, Nancy Craig5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3204; 2: *Present address: Department of Biological Engineering, Indian Institute of Technology-Gandhinagar, Ahmedabad 382424, India, Email: sharmistham@iitgn.ac.in; 3: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720-3204; 4: Université Paul Sabatier, Toulouse, France; 5: Johns Hopkins University, Baltimore, MD
  • Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
  • Received 28 February 2014 Accepted 24 July 2014 Published 05 March 2015
  • Don Rio, don_rio@berkeley.edu
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  • Abstract:

    P transposable elements were discovered in Drosophila as the causative agents of a syndrome of genetic traits called hybrid dysgenesis. Hybrid dysgenesis exhibits a unique pattern of maternal inheritance linked to the germline-specific small RNA piwi-interacting (piRNA) pathway. The use of P transposable elements as vectors for gene transfer and as genetic tools revolutionized the field of Drosophila molecular genetics. P element transposons have served as a useful model to investigate mechanisms of cut-and-paste transposition in eukaryotes. Biochemical studies have revealed new and unexpected insights into how eukaryotic DNA-based transposons are mobilized. For example, the P element transposase makes unusual 17nt-3′ extended double-strand DNA breaks at the transposon termini and uses guanosine triphosphate (GTP) as a cofactor to promote synapsis of the two transposon ends early in the transposition pathway. The N-terminal DNA binding domain of the P element transposase, called a THAP domain, contains a CCH zinc-coordinating motif and is the founding member of a large family of animal-specific site-specific DNA binding proteins. Over the past decade genome sequencing efforts have revealed the presence of P element-like transposable elements or P element transposase-like genes (called THAP9) in many eukaryotic genomes, including vertebrates, such as primates including humans, zebrafish and Xenopus, as well as the human parasite , the sea squirt , sea urchin and hydra. Surprisingly, the human and zebrafish P element transposase-related THAP9 genes promote transposition of the P element transposon DNA in human and cells, indicating that the THAP9 genes encode active P element “transposase” proteins.

  • Citation: Majumdar* S, Rio D. 2015. P Transposable Elements in and other Eukaryotic Organisms. Microbiol Spectrum 3(2):MDNA3-0004-2014. doi:10.1128/microbiolspec.MDNA3-0004-2014.

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142. Burd CG, Dreyfuss G. 1994a. RNA binding specificity of hnRNP A1: significance of hnRNP A1 high- affinity binding sites in pre-mRNA splicing. Embo J 13(5):1197–204. [PubMed]
143. Siebel CW, Admon A, Rio DC. 1995. Soma-specific expression and cloning of PSI, a negative regulator of P element pre-mRNA splicing. Genes & Development 9:269–283. [PubMed][CrossRef]
144. Labourier E, Adams MD, Rio DC. 2001. Modulation of P-element pre-mRNA splicing by a direct interaction between PSI and U1 snRNP 70K protein. Mol Cell 8(2):363–73. [PubMed][CrossRef]
145. Ignjatovic T, et al. 2005. Structural basis of the interaction between P-element somatic inhibitor and U1-70k essential for the alternative splicing of P-element transposase. J Mol Biol 351(1):52–65. [PubMed][CrossRef]
146. Min H, et al. 1997. A new regulatory protein, KSRP, mediates exon inclusion through an intronic splicing enhancer. Genes Dev 11(8):1023–1036. [PubMed][CrossRef]
147. Amarasinghe AK, et al. 2001. An in vitro-selected RNA-binding site for the KH domain protein PSI acts as a splicing inhibitor element. RNA 7(9):1239–53. [PubMed][CrossRef]
148. Chmiel NH, Rio DC, Doudna JA. 2006. Distinct contributions of KH domains to substrate binding affinity of Drosophila P-element somatic inhibitor protein. RNA 12(2):283–91. [PubMed][CrossRef]
149. Burd CG, Dreyfuss G. 1994b. Conserved structures and diversity of functions of RNA-binding proteins. Science 265(5172):615–21. [PubMed][CrossRef]
150. Kim HJ, et al. 2013. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495(7442):467–73. [PubMed][CrossRef]
151. Roche SE, Schiff M, Rio DC. 1995. P-element repressor autoregulation involves germ-line transcriptional repression and reduction of third intron splicing. Genes Dev 9(10):1278–88. [PubMed][CrossRef]
152. Adams MD, Tarng RS, Rio DC. 1997. The alternative splicing factor PSI regulates P-element third intron splicing in vivo. Genes Dev 11:129–138. [PubMed][CrossRef]
153. Hammond LE, et al. 1997. Mutations in the hrp48 gene, which encodes a Drosophila heterogeneous nuclear ribonucleoprotein particle protein, cause lethality and developmental defects and affect P-element third-intron splicing in vivo. Mol Cell Biol 17(12):7260–7267. [PubMed]
154. Labourier E, et al. 2002. The KH-type RNA-binding protein PSI is required for Drosophila viability, male fertility, and cellular mRNA processing. Genes Dev 16(1):72–84. [PubMed][CrossRef]
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156. Blanchette M, et al. 2009. Genome-wide analysis of alternative pre-mRNA splicing and RNA-binding specificities of the Drosophila hnRNP A/B family members. Mol Cell 33(4):438–49. [PubMed][CrossRef]
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/content/journal/microbiolspec/10.1128/microbiolspec.MDNA3-0004-2014
2015-03-05
2017-02-25

Abstract:

P transposable elements were discovered in Drosophila as the causative agents of a syndrome of genetic traits called hybrid dysgenesis. Hybrid dysgenesis exhibits a unique pattern of maternal inheritance linked to the germline-specific small RNA piwi-interacting (piRNA) pathway. The use of P transposable elements as vectors for gene transfer and as genetic tools revolutionized the field of Drosophila molecular genetics. P element transposons have served as a useful model to investigate mechanisms of cut-and-paste transposition in eukaryotes. Biochemical studies have revealed new and unexpected insights into how eukaryotic DNA-based transposons are mobilized. For example, the P element transposase makes unusual 17nt-3′ extended double-strand DNA breaks at the transposon termini and uses guanosine triphosphate (GTP) as a cofactor to promote synapsis of the two transposon ends early in the transposition pathway. The N-terminal DNA binding domain of the P element transposase, called a THAP domain, contains a CCH zinc-coordinating motif and is the founding member of a large family of animal-specific site-specific DNA binding proteins. Over the past decade genome sequencing efforts have revealed the presence of P element-like transposable elements or P element transposase-like genes (called THAP9) in many eukaryotic genomes, including vertebrates, such as primates including humans, zebrafish and Xenopus, as well as the human parasite , the sea squirt , sea urchin and hydra. Surprisingly, the human and zebrafish P element transposase-related THAP9 genes promote transposition of the P element transposon DNA in human and cells, indicating that the THAP9 genes encode active P element “transposase” proteins.

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FIGURE 1

Features of the complete 2.9kb P element. A.) Sequence features of the 2.9kb P element. The four coding exons (ORF 0, 1, 2 and 3) are indicated by boxes with nucleotide numbers shown. The positions of the three introns (IVS 1, 2, 3) are indicated below. The DNA sequences of the 31bp terminal inverted repeats (TIR) and the 11bp internal inverted repeats (IIR) are shown, with corresponding nucleotide numbers shown above. The 8bp duplications of target site DNA are shown by boxes at the ends of the element. DNA binding sites for the transposase protein from the 5′ end (nt 48-68) and from the 3′ end (nt 2855-2871) that are bound by P element transposase [ 15 ]. The consensus 10bp transposase binding site is: 5′- AT(A/C)CACTTAA -3′. Distances of the beginning of the 10 bp core high affinity transposase binding sequence from the corresponding 31bp terminal repeat are indicated. Note that there are distinct spacer lengths between the 31bp repeats and the transposase binding sites, 21bp at the 5′ end and 9bp at the 3′ end, which are indicated.The sequence of the 11bp internal inverted repeats are also shown, which bind the P element THAP DNA binding domain [ 54 ]. Nucleotide numbers are from the 2907bp full-length P element sequence. B.) P element mRNAs and proteins. The 2.9kb P element and four exons (ORF 0, 1, 2 and 3) are shown at the top. The germline mRNA, in which all three introns are removed, encodes the 87kD transposase mRNA. The somatic mRNA, in which only the first two introns are removed (and which is also expressed in germline as well as somatic cells), encodes the 66kD repressor mRNA. Shown at the bottom is a KP element, which contains an internal deletion. This truncated element encodes a 24kD repressor protein. doi:10.1128/microbiolspec.MDNA3-0004-2014.f1

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 2

THAP domain-containing proteins in the human genome. Diagram of the 12 human THAP domain-containing proteins and P element transposase. Note that the homology of human THAP9 and the Drosophila P element transposase extends the entire length of the protein, well beyond the N-terminal THAP DNA binding domain. Taken from [ 28 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f2

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 3a

Organization of the zebrafish Pdre P element-like elements and activity of human THAP9 with Drosophila P element DNA. A.) Organization of the zebrafish Pdre inverted repeat elements. Indicated are the 8bp target site duplication (TSD), 13bp terminal inverted repeat (TIR) and 12bp internal inverted repeat (STR) [ 33 ].doi:10.1128/microbiolspec.MDNA3-0004-2014.f3a

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 3b

Organization of the zebrafish Pdre P element-like elements and activity of human THAP9 with Drosophila P element DNA. B.) Assay for THAP9 transposition of Drosophila P element DNA in human cells HEK 293 cells. A P element vector (Cg4) carrying the G-418 gene is transfected into human cells along with expression vectors for P element transposase or human THAP9. Upon G-418 selection, individual colonies are assayed for novel DNA insertion sites [ 35 ].doi:10.1128/microbiolspec.MDNA3-0004-2014.f3b

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 3c

Organization of the zebrafish Pdre P element-like elements and activity of human THAP9 with Drosophila P element DNA. C.) Colonies of human cells in which P elements have undergone transposition by P element transposase or human THAP9 compared to a negative control plate [ 35 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f3c

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 4

P element-mediated germline transformation. Outline of the method for germline transformation of using P element vectors. Two plasmids, one encoding the P element transposase protein but lacking P element ends and the second plasmid carrying a foreign DNA segment and an eye color marker gene ( or ) within P element ends, are injected into the posterior pole of pre-blastoderm embryos. Once the transposase plasmid enters nuclei of presumptive germline cells and is expressed, it leads to transposition of the P element from the second plasmid into germline chromosomes. Following development of the injected embryos (G generation), the surviving adults are mated to or flies (G generation) and the progeny from this cross (G generation) are scored for restoration of wild type eye color. The transformation frequency is typically ∼20% of the fertile G adults are carrying the transgene [ 37 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f4

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 5a

Domain organization of the P element transposase protein. A.) Domains of P element transposase. The N-terminal region contains a CCH motif and basic region, called the THAP domain, involved in site-specific DNA binding. There are two dimerization regions adjacent to the N-terminal DNA binding domain: dimerization region I is a canonical leucine zipper motif and dimerization region II is C-terminal to the leucine zipper but does not resemble any known motif. The central part of the protein contains a GTP binding region, with some sequence motifs found in the GTPase superfamily [ 61 ]. Acidic residues are enriched at the C-terminus. doi:10.1128/microbiolspec.MDNA3-0004-2014.f5a

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 5b

Domain organization of the P element transposase protein. B.) Similarities between P element transposase and GTPase superfamily members. Alignments of regions of P element transposase that bear some resemblance to known G proteins. The conserved motifs for phosphoryl binding and guanine specificity are indicated at the top. Amino acid numbers are given below for ras, T antigen and P element transposase. The residue D379 that when changed to N (aspartic acid to asparagine) switched the nucleotide specificity from guanosine to xanthosine in P element transposase is indicated at the bottom. Figure taken from [ 61 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f5b

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 5c

Domain organization of the P element transposase protein. C.) Sequence of the P element transposase with predicted secondary structural elements and putative catalytic signature residues. Taken from [ 71 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f5c

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 6a

Pathway of DNA cleavage and joining and transposase-DNA assembly during P element transposition. A.) Shown at the top is the P element donor site with the target site duplications, 31bp inverted repeats and the 5′ and 3′ cleavage sites indicated. In the first step of transposition, donor cleavage occurs and both ends of the P element are cleaved. This novel DNA cleavage results in a 17nt single-strand extension on the P element transposon ends and leaves 17nt of single-stranded DNA from each P element inverted repeat attached to the flanking donor DNA cleavage site. Once transposon excision occurs, the donor site can be repaired via a non-homologous end joining (NHEJ) pathway (shown to the right) or via the synthesis-dependent strand annealing (SDSA) homology-dependent repair pathway (not shown) [157]. The excised P element then selects a target site and the strand transfer reaction integrates the P element into the donor site generating a gapped intermediate, which upon DNA repair completes integration creating a direct 8bp duplication of target DNA flanking the new P element insertion (bottom). Figure taken from [ 74 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f6a

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 6b

Pathway of DNA cleavage and joining and transposase-DNA assembly during P element transposition. B.) Synaptic and cleaved donor DNA intermediates detected by atomic force microscopy (AFM). Taken from [ 63 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f6b

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 6c

Pathway of DNA cleavage and joining and transposase-DNA assembly during P element transposition. C.) Single-end transposon binding of transposase in the absence of GTP. AFM imaging of P element DNA in the presence of transposase and in the absence of GTP. Taken from [ 62 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f6c

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 7

Overall structure of Drosophila P element transposase THAP domain (DmTHAP)-DNA complex. A.) The protein-DNA interface. Experimental electron density map of the DNA (blue mesh) is contoured at 1.5σ. DmTHAP is shown as a ribbon diagram and labeled by secondary structure, with the β–α–β motif highlighted in magenta. Zinc is shown as a green sphere. B.) Base-specific interactions in the major and minor groove. Interacting amino acids are shown as magenta sticks; DNA is shown in blue surface representation; zinc-coordinating residues are shown as green sticks. C.) Structure-based multiple sequence alignment of DmTHAP, human THAP1, 2, 7, 9 and 11, and CtBP. Conserved residues are highlighted; zinc-coordinating CCH motif is highlighted in green and indicated by green circles; DNA-binding residues of DmTHAP are indicated by magenta circles and are labeled. The secondary structure diagram is shown for DmTHAP and labeled as in (A). Taken from [ 57 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f7

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 8

Base-specific DmTHAP-DNA contacts. A.) Schematic representation of all base-specific contacts in the major and minor groove. Direct contacts are shown as solid lines, base-specific water-mediated contacts are shown as dashed lines, interacting phosphates are highlighted yellow. B.) Surface representation of DmTHAP. Sequence specific DNA-binding residues are highlighted in magenta. DNA backbone is shown as lines with sub-site positions labeled. Taken from [ 57 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f8

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 9

Consensus target site for P element integration. A 14bp palindromic motif deduced from analysis of > 20,000 P element insertions displayed as a position-specific scoring matrix (PSSM). Taken from [ 55 , 56 ] and C. Bergman, personal communication. doi:10.1128/microbiolspec.MDNA3-0004-2014.f9

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 10

Homology-dependent gap repair following P element excision via the SDSA (synthesis-dependent strand annealing) pathway. Homologous chromosomes or sister chromatids, which after undergoing P element excision leave a double strand gap at the donor site. The homologous sequence then serves as a template for synthesis dependent strand annealing synthesis (SDSA) [ 91 , 93 , 157]. Completion of DNA repair replaces the original P element with a newly synthesized copy. If DNA synthesis during this gap repair process is incomplete, internal deletions of the P element would result. doi:10.1128/microbiolspec.MDNA3-0004-2014.f10

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 11

The genetics and symptoms of hybrid dysgenesis. The reciprocal crosses of hybrid dysgenesis are shown. Only when P strain males are mated to M strain females does abnormal germline development occur, due to high rates of P element transposition. Progeny from reciprocal M male by P female, P × P or M × M crosses are normal. M females give rise to eggs with a state permissive for P element transposition (M cytotype) whereas P females give rise to eggs with a state restrictive for P element transposition (P cytotype). doi:10.1128/microbiolspec.MDNA3-0004-2014.f11

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 12a

Model for somatic inhibition of IVS3 splicing and splicing factors involved. A.) U1 snRNP (small nuclear ribonucleoprotein particle) normally interacts with the IVS3 5′ splice site (5′ SS) during the early steps of intron recognition and spliceosome assembly. In somatic cells (and ) this site is blocked [ 137 ]. Mutations in the upstream negative regulatory element lead to activation of IVS3 splicing [ 134 ] and [ 137 , 138 ]. The F1 site is known to bind U1 snRNP [ 137 , 144 ] and the F2 site is known to bind the hnRNP protein, hrp48 [ 139 ]. An RNA binding protein containing four KH-domains which is expressed highly in somatic cells, called PSI, has also been implicated in IVS3 splicing control [ 143 ]. doi:10.1128/microbiolspec.MDNA3-0004-2014.f12a

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014
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FIGURE 12b

Model for somatic inhibition of IVS3 splicing and splicing factors involved. B.) Diagram of the domain organization of PSI and hrp48. PSI contains four N-terminal KH-type RNA binding domains and a reiterated 100 amino segment (A and B domains) that interacts with the U1 snRNP 70K protein. Hrp48 contains two N-terminal RRM-type RNA binding domains and a low complexity (RGG) glycine-rich C-terminal domain. doi:10.1128/microbiolspec.MDNA3-0004-2014.f12b

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Tables

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TABLE I

Genetic assays for P cytotype repression

Source: microbiolspec March 2015 vol. 3 no. 2 doi:10.1128/microbiolspec.MDNA3-0004-2014

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