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Transposons: Mobile DNA Transposons are segments of DNA that can move around to different positions in the genome of a single cell. In the process, they may •cause mutations •increase (or decrease) the amount of DNA in the genome 1 These mobile segments of DNA are sometimes called "jumping genes". There are two distinct types of transposons: • DNA transposons - transposons consisting only of DNA that moves directly from place to place. •Retrotransposons that ~first transcribe the DNA into RNA and then ~use reverse transcriptase to make a DNA copy of the RNA to insert in a new location. Classification of transposons into two classes In both cases ds DNA intermediate is integrated into the target site in DNA to complete movement 2 DNA transposons are able to transpose in direct, DNA-DNA manner and are present in prokaryotes and eukaryotes Two distinct mechanisms of transposition: •Replicative transposition – direct interaction between the donor transposon and the target site, resulting in copying of the donor element •Conservative transposition – involving excision of the element and reintegration at a new site. DNA transposons of prokaryotes ITR Insertion sequence Composite transposon Tn3-type transposon AB resistance gene IS ~ 0.3-up to 2kb 2.5-10kb IS ITR ITR transposase ITR Transposable phage ITR transposase Integration and replication genes resolvase AB resistance gene Lysis genes ~5kb ITR Protein coat genes ~38kb 3 Non-replicative transposition of bacterial insertion sequence Enzyme that catalyses transposition – transposase. Bacterial transposon – composite transposon Note – internal inverted repeats of IS1 abutting the resistance gene are so mutated, that transposase does not recognize them. IS element transposase makes cuts at positions of red arrows and entire transposon is moved to the donor site. 4 Transposition via RNA intermediate Retrotransposons Retrotransposons move by a "copy and paste" mechanism but in contrast to the transposons described above, the copy is made of RNA, not DNA. 40% of the entire human genome consists of retrotransposons. Retroelements LTR gag pol env LTR Retrovirus LTR gag pol LTR Ty1/copia retroelement gag? pol poly(A) LINE SINE poly(A) 5 RNA transposons or retroelements are features of eukaryotic genome, they are not found in prokaryotes. Great deal of attention: attention because of similarities to retroviruses. General structure of eukaryotic viral retrotransposons LTrs – are also present in retroviral DNA. Like other transposons, they have short target –site direct repeats. The basic mechanism – three steps: 1. An RNA copy of transposon is synthesized by the normal process of transcription. 2. The RNA transcript is copied into DNA, which initially exists as an independent molecule outside of the genome. This conversion of RNA to DNA, the reverse of normal transcription process required reverse transcriptase. It is often coded by a gene within the transposon and is translated from the RNA copy synthesized instep 1. 3. The DNA copy of the transposon integrates into the genome, possibly back into the same chromosome occupied by original unit, or by another chromosome. 6 Generation of retroviral genomic RNA from integrated retroviral DNA Left LTR functions as a promoter that directs host cell RNA polymerase II to initiate transcription at 5’ nt of R. After all is transcribed, the right sequence directs host cell processing enzymes to cleave primary transcript and add polyA tail to the end of R sequence. The resulting retroviral RNA genome lacks complete LTRs. However, after virus enters the cell genome, reverse transcription by virus encoded RT yields a a dsDNA with LTRs. Intergase, coded by retrovirus, inserts the ds retroviral DNA into genome. And short target sequence repeats are generated. Like retroviruses, Ty and copia encode RT and integrase. General structure of an L1 LINE element – a common type of non-viral retrotransposon ORF1 – encodes and RNA binding protein; ORF2 – protein similar to reverse transcriptase. NO LRTs, but AT reach region is thought to function in transposition. 7 Transposable elements and genome dynamics Transposition and host genome •Mutation •Accumulation •Sequence duplication •Horizontal transfer •Host defense Safe-haven hypothesis Transposable elements select integration sites that minimize genetic damage to the host References Lodish et al., Molecular Cell Biology, 5th edition. T. A. Brown, Genomes, 1999, Wiley-Liss, New-York. Nature Reviews Molecular Cell Biology 2; 151-155 (2001). Weaver, Molecular Biology, 2005, McGraw Hill. Peterson-Burch, B.D., Wright, D.A., Laten, H.M. &.Voytas, D.F. 2000. “Retroviruses in Plants?” Trends Genet. 16: 151-152 8