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Long Interspersed Nucleotide Elements (LINEs)

Long Interspersed Nucleotide Elements (LINEs). Rami Al- Ouran. Introduction. Transposable elements (TEs) occupy 46% of the human genome Two classes of TEs: DNA transposons RNA transposons ( retrotransposons or retroelements ) Retroelements : Long terminal repeats (LTR)

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Long Interspersed Nucleotide Elements (LINEs)

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  1. Long Interspersed Nucleotide Elements (LINEs) Rami Al-Ouran

  2. Introduction • Transposable elements (TEs) occupy 46% of the human genome • Two classes of TEs: • DNA transposons • RNA transposons (retrotransposons or retroelements) • Retroelements: • Long terminal repeats (LTR) • non-LTR (LINE) • LINEs occupy over 35% of the human genome!!!

  3. Introduction • Non-LTR include: • Autonomous members: Long Interspersed Elements (LINE) • Non autonomous members: ALU, SINE • In mammals LINE1 is the predominant LINE element • TE activity leads to: • Genomic mutations • Interference with gene expression

  4. Definition of LINE1 • LINE1 is • an autonomous TE • about 6 kb long • that propagates in the genome by making RNA copies of themselves • and then reverse transcribed and integrated into the genome. • Encodes two open reading frames ORF1 and ORF2 required for L1 retransposition From Belancio et al., GenomeMedicine1:97, (2009)

  5. Structure of LINE1 5’UTR ORF1 ORF2 3’UTR 5’UTR that contains an internal promoter ORF1 which encodes protein ORF1p or p40 Inter-ORF linker region ORF2 which encodes ORF2p 3’UTR containing a functional polyadenylation signal

  6. Lifecycle of LINE1 From Belancio et al., GenomeMedicine1:97, (2009)

  7. L1 integration reaction. From Babushok et al. Human Mutation (2007)

  8. Lifecycle of LINE1 • Transcription. Initiation of transcription. • Before leaving the nucleus the number of of L1 transcripts can be reduced by RNA processing • Translation. L1 enters the cytoplasm for translation to produce ORF1 and ORF2 proteins are produced which are needed for retransposition. RNP(ribonucleoprotein particle) is formed • Insertion of new L1 copy. This could lead to DSB or to TPRT (Target Primed Reverse Transcription)

  9. LINE1 and Disease • Insertion of new element copies • In 1991 the discovery of first known active human L1 was from its retrotransposition into the factor VIII gene causing hemophilia • The random insertion process leads to diversity in gene diseases • In breast cancer BRCA1 and BRCA2 are disrupted by TE insertion • Interference with gene expression • Insertion of the retroelement disrupts the gene function and gene expression

  10. LINE1 and DSBs • Formation of DNA DSBs is associated with L1 expression • Depends on the enzymatic activity of the L1 ORF2 endonuclease domain

  11. Conclusions • LINEs are long interspersed retro elements • Account for almost 35% of human genome • LINE1 can cause human disease by insertion and modifying gene expression • LINE1 can lead to DSB

  12. References • Belancio VP, Deininger PL, Roy-Engel AM: LINE dancing in the human genome: transposable elements and disease. Genome Med. (2009) Oct 27;1(10):97. • Babushok, D. V. and Kazazian, H. H. (2007), Progress in understanding the biology of the human mutagen LINE-1. Human Mutation, 28: 527–539. doi: 10.1002/humu.20486

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