Identification of LEDGF/p75 as novel host factor of L1 retrotransposition

Saskia Lesire
Persbericht

Retrotransposons en HIV: meer gelijkenissen dan gedacht?

De evolutie van de mens is een proces dat nog steeds aan de gang is. Verschillen in ons DNA zorgen voor diversiteit tussen individuen en maken ons vanuit darwinistisch perspectief meer aangepast aan onze leefomgeving. Retrotransposons zijn een van de drijvers van dit dynamisch proces. Hoewel ze hun belang hebben aangetoond in de evolutie van de mens, is over retrotransposons slechts het tipje van de ijsberg gekend. 

Al in 1948, nog voor de structuur van DNA ontdekt werd, deed Barbara McClintock onderzoek in genetica. Haar baanbrekende studie over mobiele stukjes DNA, die ze later transposons noemde, werd met veel ongeloof ontvangen. In die tijd werd immers gedacht dat DNA statisch was, en mobiele DNA fragmenten pasten de facto niet in dat plaatje. McClintock kreeg pas na lange tijd erkenning en uiteindelijk ook een Nobelprijs voor haar werk, dat tot op vandaag invloed heeft op onze kennis van het menselijk DNA. 

Springende genen in het menselijk DNA: een korte introductie

DNA is de drager van erfelijke informatie en bevindt zich in de kern van onze cellen. DNA wordt doorgegeven van generatie op generatie, maar ondergaat hierbij ook enkele veranderingen. Een van de mechanismen achter deze veranderingen is transpositie. Zoals de naam al doet vermoeden, zijn transposons fragmenten DNA die zich op een andere plek inbouwen in het DNA. Ze zijn beter bekend als ‘springende genen’ door hun vermogen om te ‘springen’ tussen verschillende locaties in het DNA. Op deze manier veranderen ze het erfelijk materiaal dat aan de volgende generatie wordt doorgegeven. 

Retrotransposons zijn een subcategorie van transposons. Ze werken via een kopieer-en-plak mechanisme, met als gevolg dat ons DNA steeds uitbreidt (zie figuur 1). Vergelijk het met een boek waarvan je een pagina kopieert en op een willekeurige plaats in het boek terugzet. Misschien zal het je verassen, maar wel 40% van ons DNA bestaat uit retrotransposons.

Figuur 1

Figuur 1: Retrotranspositie in de cel. 

Recent onderzoek toonde aan dat retrotransposons voornamelijk actief zijn in de hersenen en een rol spelen in geheugenvorming. Het proces van retrotranspositie heeft echter ook een keerzijde. De sprong van een retrotransposon naar een ongewenste plaats in ons DNA kan een waaier aan ziekten veroorzaken. Voorbeelden hiervan zijn kanker, Rett syndroom en schizofrenie. Steeds meer studies wijzen op het belang van een goede balans in het proces van retrotranspositie zodat het niet te weinig optreedt, maar vooral ook niet te veel. Doorheen de evolutie hebben onze cellen zich aangepast om dit proces onder controle te houden waardoor de schade doorgaans gelimiteerd blijft. 

Retrotranspositie: een proces met veel ontbrekende puzzelstukken

Hoewel het proces van retrotranspositie al langer gekend is, komen we nog veel kennis tekort over de exacte functie en het werkingsmechanisme van retrotransposons. Welke eiwitten hebben retrotransposons nodig om zich te verplaatsen? Welke eiwitten houden retrotransposons net tegen om te springen? Deze kennis hebben we nodig om te begrijpen hoe retrotransposons werken en wat er exact gebeurt wanneer het misloopt. 

Gelijkenissen tussen LINE-1 retrotransposons en HIV

LINE-1 retrotransposons zijn de enige transposons die nog steeds actief zijn in menselijke cellen. Hoewel LINE-1 retrotransposons van nature voorkomen in ons DNA, vertonen ze qua structuur sterke gelijkenissen met het humaan immunodeficiëntievirus (HIV), het virus dat aids veroorzaakt. HIV maakt gebruik van de aanwezige infrastructuur in de cel om zich te vermeerderen. Net zoals HIV hebben LINE-1 retrotransposons deze infrastructuur nodig om te kunnen springen. Deze interessante gelijkenis vormde het onderzoeksvraagstuk van mijn thesis. We bestudeerden eiwitten die een rol spelen bij een HIV infectie en onderzochten of deze ook een rol spelen in LINE-1 retrotranspositie. 

Het meten van retrotranspositieactiviteit

Voor ons onderzoek hebben we een methode geoptimaliseerd waarbij we de activiteit van het LINE-1 retrotransposon konden meten. Door het retrotransposon te labelen met een groen fluorescent eiwit, kregen cellen een groene kleur wanneer het LINE-1 retrotransposon ‘springt’. Daarna konden we meten hoeveel cellen in het staal groen kleuren. 

In een volgende stap werd er met behulp van biotechnologische hulpmiddelen één eiwit in de cel uitgeschakeld en konden we meten of dit een effect heeft op LINE-1 retrotranspositie (zie figuur 2). Wanneer we een stijging in het aantal groene cellen observeerden, had het eiwit een onderdrukkende functie. Omgekeerd, wanneer we een daling in het aantal groene cellen observeerden, had het eiwit een stimulerende functie. 

Figuur 2

Figuur 2: De LINE-1 retrotranspositie assay: een methode om LINE-1 activiteit in cellen te bestuderen.

Het eiwit LEDGF/p75 stimuleert LINE-1 retrotranspositie

HIV virussen zijn uniek doordat ze hun eigen virale DNA inbouwen in het DNA van de gastheercel. Het virus heeft hiervoor de hulp nodig van enkele eiwitten in de cel. Een van deze eiwitten is LEDGF/p75 dat bindt aan het viraal DNA en helpt bij de inbouwen in het gastheer DNA. Deze interactie maakt van LEDGF/p75 dan ook een veelbelovend doelwit bij de zoektocht naar een geneesmiddel tegen HIV. 

Vertrekkend vanuit de gelijkenissen tussen HIV en LINE-1 bestudeerden we de functie van LEDGF/p75 in LINE-1 retrotranspositie. De resultaten wezen erop dat LEDGF/p75 stimulerend werkte op LINE-1 retrotranspositie. LEDGF/p75 zorgt dus voor meer retrotranspositie in onze cellen. Een intrigerende bevinding die veel vragen oproept. In welke stap van de retrotranspositiecyclus speelt LEDGF/p75 een rol? Hoe interageert LEDGF/p75 met het retrotransposon? Zijn er nog andere eiwitten bij betrokken? De resultaten geven ons in ieder geval veel stof tot nadenken. 

De eerste stappen van een lange weg

Deze studie zet slechts de eerste stappen in het onderzoek naar eiwitten die een rol spelen in LINE-1 retrotranspositie. De overeenkomsten tussen LINE-1 en HIV dagen ons uit om dit verder te onderzoeken. Wellicht is de ontbrekende kennis over retrotransposons te vinden bij onze kennis over HIV. Momenteel moeten we echter genoegen nemen met het besef dat retrotranspositie in onze hersenen gebeurt zonder dat we er veel over weten. Misschien zijn retrotransposons net nodig om je dit artikel te kunnen herinneren? De toekomst zal het uitwijzen. 

Bibliografie
  1. McClintock B. Controlling elements and the gene. Cold Spring Harb Symp Quant Biol. 1956;21:197-216.

  2. Cordaux R, Batzer MA. The impact of retrotransposons on human genome evolution. Nat Rev Genet. 2009;10(10):691-703.

  3. Garcia Perez JL. Transposons and retrotransposons : methods and protocols. Springer. 2016.

  4. Singer T, McConnell MJ, Marchetto MC, Coufal NG, Gage FH. LINE-1 retrotransposons:

    mediators of somatic variation in neuronal genomes? Trends Neurosci. 2010;33(8):345-54.

  5. Thomas CA, Paquola AC, Muotri AR. LINE-1 retrotransposition in the nervous system. Annu

    Rev Cell Dev Biol. 2012;28:555-73.

  6. Suarez NA, Macia A, Muotri AR. LINE-1 retrotransposons in healthy and diseased human

    brain. Dev Neurobiol. 2018;78(5):434-55.

  7. Thomas CA, Muotri AR. LINE-1: creators of neuronal diversity. Front Biosci (Elite Ed).

    2012;4:1663-8.

  8. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing

    and analysis of the human genome. Nature. 2001;409(6822):860-921.

  9. Brouha B, Schustak J, Badge RM, Lutz-Prigge S, Farley AH, Moran JV, et al. Hot L1s account for the bulk of retrotransposition in the human population. Proc Natl Acad Sci U S A.

    2003;100(9):5280-5.

  10. Human retrotransposons in health and disease. Springer. 2019.

  11. Muotri AR, Marchetto MC, Coufal NG, Gage FH. The necessary junk: new functions for

    transposable elements. Hum Mol Genet. 2007;16 Spec No. 2:R159-67.

  12. Ohshima K, Hattori M, Yada T, Gojobori T, Sakaki Y, Okada N. Whole-genome screening indicates a possible burst of formation of processed pseudogenes and Alu repeats by particular

    L1 subfamilies in ancestral primates. Genome Biol. 2003;4(11):R74.

  13. Ostertag EM, DeBerardinis RJ, Goodier JL, Zhang Y, Yang N, Gerton GL, et al. A mouse

    model of human L1 retrotransposition. Nat Genet. 2002;32(4):655-60.

  14. Lazaros L, Kitsou C, Kostoulas C, Bellou S, Hatzi E, Ladias P, et al. Retrotransposon expression and incorporation of cloned human and mouse retroelements in human spermatozoa.

    Fertil Steril. 2017;107(3):821-30.

  15. Malki S, van der Heijden GW, O'Donnell KA, Martin SL, Bortvin A. A role for retrotransposon

    LINE-1 in fetal oocyte attrition in mice. Dev Cell. 2014;29(5):521-33.

  16. Wang L, Dou K, Moon S, Tan FJ, Zhang ZZ. Hijacking Oogenesis Enables Massive

    Propagation of LINE and Retroviral Transposons. Cell. 2018;174(5):1082-94 e12.

  17. Kano H, Godoy I, Courtney C, Vetter MR, Gerton GL, Ostertag EM, et al. L1 retrotransposition occurs mainly in embryogenesis and creates somatic mosaicism. Genes & development.

    2009;23(11):1303-12.

  18. Garcia-Perez JL, Marchetto MC, Muotri AR, Coufal NG, Gage FH, O'Shea KS, et al. LINE-1

    retrotransposition in human embryonic stem cells. Hum Mol Genet. 2007;16(13):1569-77.

  19. van den Hurk JAJM, Meij IC, del Carmen Seleme M, Kano H, Nikopoulos K, Hoefsloot LH, et al. L1 retrotransposition can occur early in human embryonic development. Human

    Molecular Genetics. 2007;16(13):1587-92.

  20. De S. Somatic mosaicism in healthy human tissues. Trends Genet. 2011;27(6):217-23.

  21. Coufal NG, Garcia-Perez JL, Peng GE, Yeo GW, Mu Y, Lovci MT, et al. L1 retrotransposition

    in human neural progenitor cells. Nature. 2009;460(7259):1127-31.

  22. Macia A, Widmann TJ, Heras SR, Ayllon V, Sanchez L, Benkaddour-Boumzaouad M, et al.

    Engineered LINE-1 retrotransposition in nondividing human neurons. Genome Res. 2017;27(3):335-48.

  1. Muotri AR, Chu VT, Marchetto MC, Deng W, Moran JV, Gage FH. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature. 2005;435(7044):903-10.

  2. Upton KR, Gerhardt DJ, Jesuadian JS, Richardson SR, Sanchez-Luque FJ, Bodea GO, et al. Ubiquitous L1 mosaicism in hippocampal neurons. Cell. 2015;161(2):228-39.

  3. Han JS, Szak ST, Boeke JD. Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes. Nature. 2004;429(6989):268-74.

  4. Bachiller S, Del-Pozo-Martin Y, Carrion AM. L1 retrotransposition alters the hippocampal genomic landscape enabling memory formation. Brain Behav Immun. 2017;64:65-70.

  5. Muotri AR, Zhao C, Marchetto MC, Gage FH. Environmental influence on L1 retrotransposons in the adult hippocampus. Hippocampus. 2009;19(10):1002-7.

  6. Ponomarev I, Rau V, Eger EI, Harris RA, Fanselow MS. Amygdala transcriptome and cellular mechanisms underlying stress-enhanced fear learning in a rat model of posttraumatic stress disorder. Neuropsychopharmacology. 2010;35(6):1402-11.

  7. Hunter RG, Murakami G, Dewell S, Seligsohn M, Baker ME, Datson NA, et al. Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response. Proc Natl Acad Sci U S A. 2012;109(43):17657-62.

  8. Ponomarev I, Wang S, Zhang L, Harris RA, Mayfield RD. Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J Neurosci. 2012;32(5):1884-97.

  9. Nigumann P, Redik K, Matlik K, Speek M. Many human genes are transcribed from the antisense promoter of L1 retrotransposon. Genomics. 2002;79(5):628-34.

  10. Kolosha VO, Martin SL. In vitro properties of the first ORF protein from mouse LINE-1 support its role in ribonucleoprotein particle formation during retrotransposition. Proc Natl Acad Sci U S A. 1997;94(19):10155-60.

  11. Mathias SL, Scott AF, Kazazian HH, Jr., Boeke JD, Gabriel A. Reverse transcriptase encoded by a human transposable element. Science. 1991;254(5039):1808-10.

  12. Feng Q, Moran JV, Kazazian HH, Jr., Boeke JD. Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell. 1996;87(5):905-16.

  13. Denli AM, Narvaiza I, Kerman BE, Pena M, Benner C, Marchetto MC, et al. Primate-specific ORF0 contributes to retrotransposon-mediated diversity. Cell. 2015;163(3):583-93.

  14. Yang N, Kazazian HH, Jr. L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nat Struct Mol Biol. 2006;13(9):763-71.

  15. Alisch RS, Garcia-Perez JL, Muotri AR, Gage FH, Moran JV. Unconventional translation of mammalian LINE-1 retrotransposons. Genes Dev. 2006;20(2):210-24.

  16. Kulpa DA, Moran JV. Ribonucleoprotein particle formation is necessary but not sufficient for LINE-1 retrotransposition. Hum Mol Genet. 2005;14(21):3237-48.

  17. Wei W, Gilbert N, Ooi SL, Lawler JF, Ostertag EM, Kazazian HH, et al. Human L1 retrotransposition: cis preference versus trans complementation. Mol Cell Biol. 2001;21(4):1429-39.

  18. Garcia-Perez JL, Doucet AJ, Bucheton A, Moran JV, Gilbert N. Distinct mechanisms for trans- mediated mobilization of cellular RNAs by the LINE-1 reverse transcriptase. Genome Res. 2007;17(5):602-11.

  19. Dai L, Taylor MS, O'Donnell KA, Boeke JD. Poly(A) binding protein C1 is essential for efficient L1 retrotransposition and affects L1 RNP formation. Mol Cell Biol. 2012;32(21):4323- 36.

  20. Cost GJ, Feng Q, Jacquier A, Boeke JD. Human L1 element target-primed reverse transcription in vitro. EMBO J. 2002;21(21):5899-910.

  21. Ostertag EM, Kazazian HH, Jr. Biology of mammalian L1 retrotransposons. Annu Rev Genet. 2001;35:501-38.

  1. Levin HL, Moran JV. Dynamic interactions between transposable elements and their hosts. Nat Rev Genet. 2011;12(9):615-27.

  2. Mita P, Boeke JD. How retrotransposons shape genome regulation. Curr Opin Genet Dev. 2016;37:90-100.

  3. Hatanaka Y, Inoue K, Oikawa M, Kamimura S, Ogonuki N, Kodama EN, et al. Histone chaperone CAF-1 mediates repressive histone modifications to protect preimplantation mouse embryos from endogenous retrotransposons. Proc Natl Acad Sci U S A. 2015;112(47):14641- 6.

  4. Muotri AR, Marchetto MC, Coufal NG, Oefner R, Yeo G, Nakashima K, et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature. 2010;468(7322):443-6.

  5. Nan X, Campoy FJ, Bird A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell. 1997;88(4):471-81.

  6. Yu F, Zingler N, Schumann G, Stratling WH. Methyl-CpG-binding protein 2 represses LINE- 1 expression and retrotransposition but not Alu transcription. Nucleic Acids Res. 2001;29(21):4493-501.

  7. Della Ragione F, Vacca M, Fioriniello S, Pepe G, D'Esposito M. MECP2, a multi-talented modulator of chromatin architecture. Brief Funct Genomics. 2016;15(6):420-31.

  8. Skene PJ, Illingworth RS, Webb S, Kerr AR, James KD, Turner DJ, et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol Cell. 2010;37(4):457-68.

  9. Kriaucionis S, Bird A. The major form of MeCP2 has a novel N-terminus generated by alternative splicing. Nucleic Acids Res. 2004;32(5):1818-23.

  10. Lewis JD, Meehan RR, Henzel WJ, Maurer-Fogy I, Jeppesen P, Klein F, et al. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell. 1992;69(6):905-14.

  11. Saleh A, Macia A, Muotri AR. Transposable Elements, Inflammation, and Neurological Disease. Front Neurol. 2019;10:894.

  12. Castro-Diaz N, Ecco G, Coluccio A, Kapopoulou A, Yazdanpanah B, Friedli M, et al. Evolutionally dynamic L1 regulation in embryonic stem cells. Genes Dev. 2014;28(13):1397- 409.

  13. Kuwabara T, Hsieh J, Muotri A, Yeo G, Warashina M, Lie DC, et al. Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nat Neurosci. 2009;12(9):1097-105.

  14. Pizarro JG, Cristofari G. Post-Transcriptional Control of LINE-1 Retrotransposition by Cellular

    Host Factors in Somatic Cells. Front Cell Dev Biol. 2016;4:14.

  15. Belancio VP, Hedges DJ, Deininger P. LINE-1 RNA splicing and influences on mammalian

    gene expression. Nucleic Acids Res. 2006;34(5):1512-21.

  16. Belancio VP, Roy-Engel AM, Deininger P. The impact of multiple splice sites in human L1

    elements. Gene. 2008;411(1-2):38-45.

  17. Goodier JL. Restricting retrotransposons: a review. Mob DNA. 2016;7:16.

  18. Toth KF, Pezic D, Stuwe E, Webster A. The piRNA Pathway Guards the Germline Genome

    Against Transposable Elements. Adv Exp Med Biol. 2016;886:51-77.

  19. Russell SJ, Stalker L, LaMarre J. PIWIs, piRNAs and Retrotransposons: Complex battles during reprogramming in gametes and early embryos. Reprod Domest Anim. 2017;52 Suppl

    4:28-38.

  20. Roberts JT, Cardin SE, Borchert GM. Burgeoning evidence indicates that microRNAs were

    initially formed from transposable element sequences. Mob Genet Elements. 2014;4:e29255.

  21. Khazina E, Truffault V, Buttner R, Schmidt S, Coles M, Weichenrieder O. Trimeric structure and flexibility of the L1ORF1 protein in human L1 retrotransposition. Nat Struct Mol Biol.

    2011;18(9):1006-14.

  1. Taylor MS, LaCava J, Mita P, Molloy KR, Huang CR, Li D, et al. Affinity proteomics reveals human host factors implicated in discrete stages of LINE-1 retrotransposition. Cell. 2013;155(5):1034-48.

  2. Moldovan JB, Moran JV. The Zinc-Finger Antiviral Protein ZAP Inhibits LINE and Alu Retrotransposition. PLoS Genet. 2015;11(5):e1005121.

  3. Goodier JL, Pereira GC, Cheung LE, Rose RJ, Kazazian HH, Jr. The Broad-Spectrum Antiviral Protein ZAP Restricts Human Retrotransposition. PLoS Genet. 2015;11(5):e1005252.

  4. Arjan-Odedra S, Swanson CM, Sherer NM, Wolinsky SM, Malim MH. Endogenous MOV10 inhibits the retrotransposition of endogenous retroelements but not the replication of exogenous retroviruses. Retrovirology. 2012;9:53.

  5. Goodier JL, Cheung LE, Kazazian HH, Jr. MOV10 RNA helicase is a potent inhibitor of retrotransposition in cells. PLoS Genet. 2012;8(10):e1002941.

  6. Li X, Zhang J, Jia R, Cheng V, Xu X, Qiao W, et al. The MOV10 helicase inhibits LINE-1 mobility. J Biol Chem. 2013;288(29):21148-60.

  7. Gregersen LH, Schueler M, Munschauer M, Mastrobuoni G, Chen W, Kempa S, et al. MOV10 Is a 5' to 3' RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3' UTRs. Mol Cell. 2014;54(4):573-85.

  8. Meister G, Landthaler M, Peters L, Chen PY, Urlaub H, Luhrmann R, et al. Identification of novel argonaute-associated proteins. Curr Biol. 2005;15(23):2149-55.

  9. Goodier JL, Zhang L, Vetter MR, Kazazian HH, Jr. LINE-1 ORF1 protein localizes in stress granules with other RNA-binding proteins, including components of RNA interference RNA- induced silencing complex. Mol Cell Biol. 2007;27(18):6469-83.

  10. Warkocki Z, Krawczyk PS, Adamska D, Bijata K, Garcia-Perez JL, Dziembowski A. Uridylation by TUT4/7 Restricts Retrotransposition of Human LINE-1s. Cell. 2018;174(6):1537-48 e29.

  11. Frost RJ, Hamra FK, Richardson JA, Qi X, Bassel-Duby R, Olson EN. MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs. Proc Natl Acad Sci U S A. 2010;107(26):11847-52.

  12. Zheng K, Xiol J, Reuter M, Eckardt S, Leu NA, McLaughlin KJ, et al. Mouse MOV10L1 associates with Piwi proteins and is an essential component of the Piwi-interacting RNA (piRNA) pathway. Proc Natl Acad Sci U S A. 2010;107(26):11841-6.

  13. Chen H, Lilley CE, Yu Q, Lee DV, Chou J, Narvaiza I, et al. APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons. Curr Biol. 2006;16(5):480-5.

  14. Esnault C, Heidmann O, Delebecque F, Dewannieux M, Ribet D, Hance AJ, et al. APOBEC3G cytidine deaminase inhibits retrotransposition of endogenous retroviruses. Nature. 2005;433(7024):430-3.

  15. Muckenfuss H, Hamdorf M, Held U, Perkovic M, Lower J, Cichutek K, et al. APOBEC3 proteins inhibit human LINE-1 retrotransposition. J Biol Chem. 2006;281(31):22161-72.

  16. Bogerd HP, Wiegand HL, Hulme AE, Garcia-Perez JL, O'Shea KS, Moran JV, et al. Cellular inhibitors of long interspersed element 1 and Alu retrotransposition. Proc Natl Acad Sci U S A. 2006;103(23):8780-5.

  17. Kinomoto M, Kanno T, Shimura M, Ishizaka Y, Kojima A, Kurata T, et al. All APOBEC3 family proteins differentially inhibit LINE-1 retrotransposition. Nucleic Acids Res. 2007;35(9):2955-64.

  18. Schumann GG. APOBEC3 proteins: major players in intracellular defence against LINE-1- mediated retrotransposition. Biochem Soc Trans. 2007;35(Pt 3):637-42.

  19. Stenglein MD, Harris RS. APOBEC3B and APOBEC3F inhibit L1 retrotransposition by a DNA deamination-independent mechanism. J Biol Chem. 2006;281(25):16837-41.

  1. Goila-Gaur R, Strebel K. HIV-1 Vif, APOBEC, and intrinsic immunity. Retrovirology. 2008;5:51.

  2. Liu C, Zhang X, Huang F, Yang B, Li J, Liu B, et al. APOBEC3G inhibits microRNA-mediated repression of translation by interfering with the interaction between Argonaute-2 and MOV10. J Biol Chem. 2012;287(35):29373-83.

  3. Xie Y, Mates L, Ivics Z, Izsvak Z, Martin SL, An W. Cell division promotes efficient retrotransposition in a stable L1 reporter cell line. Mob DNA. 2013;4(1):10.

  4. Mita P, Wudzinska A, Sun X, Andrade J, Nayak S, Kahler DJ, et al. LINE-1 protein localization and functional dynamics during the cell cycle. Elife. 2018;7.

  5. Idica A, Sevrioukov EA, Zisoulis DG, Hamdorf M, Daugaard I, Kadandale P, et al. MicroRNA miR-128 represses LINE-1 (L1) retrotransposition by down-regulating the nuclear import factor TNPO1. J Biol Chem. 2017;292(50):20494-508.

  6. Fung L, Guzman H, Sevrioukov E, Idica A, Park E, Bochnakian A, et al. miR-128 Restriction of LINE-1 (L1) Retrotransposition Is Dependent on Targeting hnRNPA1 mRNA. Int J Mol Sci. 2019;20(8).

  7. Goodier JL, Cheung LE, Kazazian HH, Jr. Mapping the LINE1 ORF1 protein interactome reveals associated inhibitors of human retrotransposition. Nucleic Acids Res. 2013;41(15):7401-19.

  8. Hamdorf M, Idica A, Zisoulis DG, Gamelin L, Martin C, Sanders KJ, et al. miR-128 represses L1 retrotransposition by binding directly to L1 RNA. Nat Struct Mol Biol. 2015;22(10):824- 31.

  9. Christ F, Thys W, De Rijck J, Gijsbers R, Albanese A, Arosio D, et al. Transportin-SR2 imports HIV into the nucleus. Current biology : CB. 2008;18(16):1192-202.

  10. Fernandez J, Machado AK, Lyonnais S, Chamontin C, Gartner K, Leger T, et al. Transportin- 1 binds to the HIV-1 capsid via a nuclear localization signal and triggers uncoating. Nat Microbiol. 2019;4(11):1840-50.

  11. Ostertag EM, Kazazian HH, Jr. Twin priming: a proposed mechanism for the creation of inversions in L1 retrotransposition. Genome Res. 2001;11(12):2059-65.

  12. Benitez-Guijarro M, Lopez-Ruiz C, Tarnauskaite Z, Murina O, Mian Mohammad M, Williams TC, et al. RNase H2, mutated in Aicardi-Goutieres syndrome, promotes LINE-1 retrotransposition. EMBO J. 2018;37(15).

  13. Bartsch K, Knittler K, Borowski C, Rudnik S, Damme M, Aden K, et al. Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy. Hum Mol Genet. 2017;26(20):3960-72.

  14. Reijns MA, Jackson AP. Ribonuclease H2 in health and disease. Biochem Soc Trans. 2014;42(4):717-25.

  15. Beilhartz GL, Gotte M. HIV-1 Ribonuclease H: Structure, Catalytic Mechanism and Inhibitors. Viruses. 2010;2(4):900-26.

  16. Choi J, Hwang SY, Ahn K. Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition. Nucleic Acids Res. 2018;46(4):1912-26.

  17. Skariah G, Seimetz J, Norsworthy M, Lannom MC, Kenny PJ, Elrakhawy M, et al. Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain. BMC Biol. 2017;15(1):54.

  18. Laguette N, Benkirane M. How SAMHD1 changes our view of viral restriction. Trends Immunol. 2012;33(1):26-33.

  19. Zhao K, Du J, Han X, Goodier JL, Li P, Zhou X, et al. Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutieres syndrome-related SAMHD1. Cell Rep. 2013;4(6):1108-15.

  1. Hu S, Li J, Xu F, Mei S, Le Duff Y, Yin L, et al. SAMHD1 Inhibits LINE-1 Retrotransposition by Promoting Stress Granule Formation. PLoS Genet. 2015;11(7):e1005367.

  2. Gramberg T, Kahle T, Bloch N, Wittmann S, Mullers E, Daddacha W, et al. Restriction of diverse retroviruses by SAMHD1. Retrovirology. 2013;10:26.

  3. Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC, Dragin L, et al. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat Immunol. 2012;13(3):223-8.

  4. Herrmann A, Wittmann S, Thomas D, Shepard CN, Kim B, Ferreiros N, et al. The SAMHD1- mediated block of LINE-1 retroelements is regulated by phosphorylation. Mob DNA. 2018;9:11.

  5. Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008;134(4):587-98.

  6. Mazur DJ, Perrino FW. Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3'-->5' exonucleases. J Biol Chem. 1999;274(28):19655-60.

  7. Jones RB, Song H, Xu Y, Garrison KE, Buzdin AA, Anwar N, et al. LINE-1 retrotransposable element DNA accumulates in HIV-1-infected cells. J Virol. 2013;87(24):13307-20.

  8. Sawyer SL, Emerman M, Malik HS. Ancient adaptive evolution of the primate antiviral DNA- editing enzyme APOBEC3G. PLoS Biol. 2004;2(9):e275.

  9. Kazazian HH, Jr., Wong C, Youssoufian H, Scott AF, Phillips DG, Antonarakis SE. Haemophilia A resulting from de novo insertion of L1 sequences represents a novel mechanism for mutation in man. Nature. 1988;332(6160):164-6.

  10. Chen JM, Stenson PD, Cooper DN, Ferec C. A systematic analysis of LINE-1 endonuclease- dependent retrotranspositional events causing human genetic disease. Hum Genet. 2005;117(5):411-27.

  11. Speek M. Antisense promoter of human L1 retrotransposon drives transcription of adjacent cellular genes. Mol Cell Biol. 2001;21(6):1973-85.

  12. Matlik K, Redik K, Speek M. L1 antisense promoter drives tissue-specific transcription of human genes. J Biomed Biotechnol. 2006;2006(1):71753.

  13. Piriyapongsa J, Marino-Ramirez L, Jordan IK. Origin and evolution of human microRNAs from transposable elements. Genetics. 2007;176(2):1323-37.

  14. Qin S, Jin P, Zhou X, Chen L, Ma F. The Role of Transposable Elements in the Origin and Evolution of MicroRNAs in Human. PLoS One. 2015;10(6):e0131365.

  15. Kines KJ, Sokolowski M, deHaro DL, Christian CM, Belancio VP. Potential for genomic instability associated with retrotranspositionally-incompetent L1 loci. Nucleic Acids Res. 2014;42(16):10488-502.

  16. Gasior SL, Wakeman TP, Xu B, Deininger PL. The human LINE-1 retrotransposon creates DNA double-strand breaks. J Mol Biol. 2006;357(5):1383-93.

  17. Wallace NA, Belancio VP, Deininger PL. L1 mobile element expression causes multiple types of toxicity. Gene. 2008;419(1-2):75-81.

  18. Balachandar V , Dhivya V , Gomathi M, Mohanadevi S, V enkatesh B, Geetha B. A review of Rett syndrome (RTT) with induced pluripotent stem cells. Stem Cell Investig. 2016;3:52.

  19. Leonard H, Cobb S, Downs J. Clinical and biological progress over 50 years in Rett syndrome. Nat Rev Neurol. 2017;13(1):37-51.

  20. Picard N, Fagiolini M. MeCP2: an epigenetic regulator of critical periods. Curr Opin Neurobiol. 2019;59:95-101.

  21. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185-8.

  1. Yusufzai TM, Wolffe AP. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000;28(21):4172-9.

  2. Gulmez Karaca K, Brito DVC, Oliveira AMM. MeCP2: A Critical Regulator of Chromatin in Neurodevelopment and Adult Brain Function. Int J Mol Sci. 2019;20(18).

  3. Ramocki MB, Tavyev YJ, Peters SU. The MECP2 duplication syndrome. Am J Med Genet A. 2010;152A(5):1079-88.

  4. Zhao B, Wu Q, Y e A Y , Guo J, Zheng X, Y ang X, et al. Somatic LINE-1 retrotransposition in cortical neurons and non-brain tissues of Rett patients and healthy individuals. PLoS Genet. 2019;15(4):e1008043.

  5. Karimi P, Kamali E, Mousavi SM, Karahmadi M. Environmental factors influencing the risk of autism. J Res Med Sci. 2017;22:27.

  6. McPartland J, Volkmar FR. Autism and related disorders. Handb Clin Neurol. 2012;106:407- 18.

  7. Shpyleva S, Melnyk S, Pavliv O, Pogribny I, Jill James S. Overexpression of LINE-1 Retrotransposons in Autism Brain. Mol Neurobiol. 2018;55(2):1740-9.

  8. Mitchell MM, Woods R, Chi LH, Schmidt RJ, Pessah IN, Kostyniak PJ, et al. Levels of select PCB and PBDE congeners in human postmortem brain reveal possible environmental involvement in 15q11-q13 duplication autism spectrum disorder. Environ Mol Mutagen. 2012;53(8):589-98.

  9. Tangsuwansri C, Saeliw T, Thongkorn S, Chonchaiya W, Suphapeetiporn K, Mutirangura A, et al. Investigation of epigenetic regulatory networks associated with autism spectrum disorder (ASD) by integrated global LINE-1 methylation and gene expression profiling analyses. PLoS One. 2018;13(7):e0201071.

  10. Nishioka M, Bundo M, Iwamoto K, Kato T. Somatic mutations in the human brain: implications for psychiatric research. Mol Psychiatry. 2019;24(6):839-56.

  11. Smigielski L, Jagannath V, Rössler W, Walitza S, Grünblatt E. Epigenetic mechanisms in schizophrenia and other psychotic disorders: a systematic review of empirical human findings. Molecular Psychiatry. 2020.

  12. Bundo M, Toyoshima M, Okada Y, Akamatsu W, Ueda J, Nemoto-Miyauchi T, et al. Increased l1 retrotransposition in the neuronal genome in schizophrenia. Neuron. 2014;81(2):306-13.

  13. Guffanti G, Gaudi S, Klengel T, Fallon JH, Mangalam H, Madduri R, et al. LINE1 insertions as a genomic risk factor for schizophrenia: Preliminary evidence from an affected family. Am J Med Genet B Neuropsychiatr Genet. 2016;171(4):534-45.

  14. Doyle GA, Crist RC, Karatas ET, Hammond MJ, Ewing AD, Ferraro TN, et al. Analysis of LINE-1 Elements in DNA from Postmortem Brains of Individuals with Schizophrenia. Neuropsychopharmacology. 2017;42(13):2602-11.

  15. Jiang T, Zong L, Zhou L, Hou Y, Zhang L, Zheng X, et al. Variation in global DNA hydroxymethylation with age associated with schizophrenia. Psychiatry Res. 2017;257:497- 500.

  16. Li S, Yang Q, Hou Y, Jiang T, Zong L, Wang Z, et al. Hypomethylation of LINE-1 elements in schizophrenia and bipolar disorder. J Psychiatr Res. 2018;107:68-72.

  17. Melas PA, Rogdaki M, Osby U, Schalling M, Lavebratt C, Ekstrom TJ. Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset. FASEB J. 2012;26(6):2712-8.

  18. Misiak B, Szmida E, Karpinski P, Loska O, Sasiadek MM, Frydecka D. Lower LINE-1 methylation in first-episode schizophrenia patients with the history of childhood trauma. Epigenomics. 2015;7(8):1275-85.

  1. Shimabukuro M, Sasaki T, Imamura A, Tsujita T, Fuke C, Umekage T, et al. Global hypomethylation of peripheral leukocyte DNA in male patients with schizophrenia: a potential link between epigenetics and schizophrenia. J Psychiatr Res. 2007;41(12):1042-6.

  2. Crow YJ, Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15(7):429-40.

  3. Volkman HE, Stetson DB. The enemy within: endogenous retroelements and autoimmune disease. Nature immunology. 2014;15(5):415-22.

  4. Orecchini E, Doria M, Antonioni A, Galardi S, Ciafre SA, Frassinelli L, et al. ADAR1 restricts LINE-1 retrotransposition. Nucleic Acids Res. 2017;45(1):155-68.

  5. Beck-Engeser GB, Eilat D, Wabl M. An autoimmune disease prevented by anti-retroviral drugs. Retrovirology. 2011;8:91.

  6. Rice GI, Meyzer C, Bouazza N, Hully M, Boddaert N, Semeraro M, et al. Reverse- Transcriptase Inhibitors in the Aicardi-Goutieres Syndrome. N Engl J Med. 2018;379(23):2275-7.

  7. Crow YJ, Leitch A, Hayward BE, Garner A, Parmar R, Griffith E, et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat Genet. 2006;38(8):910-6.

  8. Coffin SR, Hollis T, Perrino FW. Functional consequences of the RNase H2A subunit mutations that cause Aicardi-Goutieres syndrome. J Biol Chem. 2011;286(19):16984-91.

  9. Gorman JA, Hundhausen C, Errett JS, Stone AE, Allenspach EJ, Ge Y, et al. The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity. Nat Immunol. 2017;18(7):744-52.

  10. Morales DJ, Lenschow DJ. The antiviral activities of ISG15. J Mol Biol. 2013;425(24):4995- 5008.

  11. Rodriguez-Garcia E, Olague C, Rius-Rocabert S, Ferrero R, Llorens C, Larrea E, et al. TMEM173 Alternative Spliced Isoforms Modulate Viral Replication through the STING Pathway. Immunohorizons. 2018;2(11):363-76.

  12. Zheng Y, Lorenzo C, Beal PA. DNA editing in DNA/RNA hybrids by adenosine deaminases that act on RNA. Nucleic Acids Res. 2017;45(6):3369-77.

  13. Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016;11(1):159.

  14. Blocher D, Sigut D, Hannan MA. Fibroblasts from ataxia telangiectasia (AT) and AT heterozygotes show an enhanced level of residual DNA double-strand breaks after low dose- rate gamma-irradiation as assayed by pulsed field gel electrophoresis. Int J Radiat Biol. 1991;60(5):791-802.

  15. Coufal NG, Garcia-Perez JL, Peng GE, Marchetto MC, Muotri AR, Mu Y, et al. Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells. Proc Natl Acad Sci U S A. 2011;108(51):20382-7.

  16. Couratier P, Corcia P, Lautrette G, Nicol M, Marin B. ALS and frontotemporal dementia belong to a common disease spectrum. Rev Neurol (Paris). 2017;173(5):273-9.

  17. Li W, Jin Y, Prazak L, Hammell M, Dubnau J. Transposable elements in TDP-43-mediated neurodegenerative disorders. PLoS One. 2012;7(9):e44099.

  18. Liu EY, Russ J, Cali CP, Phan JM, Amlie-Wolf A, Lee EB. Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons. Cell Rep. 2019;27(5):1409-21 e6.

  19. Pereira GC, Sanchez L, Schaughency PM, Rubio-Roldan A, Choi JA, Planet E, et al. Properties of LINE-1 proteins and repeat element expression in the context of amyotrophic lateral

    sclerosis. Mob DNA. 2018;9:35.

  20. Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer's

    disease. Nat Rev Dis Primers. 2015;1:15056.

  1. Beck JA, Poulter M, Campbell TA, Uphill JB, Adamson G, Geddes JF, et al. Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease. Hum Mol Genet. 2004;13(12):1219-24.

  2. Bollati V, Galimberti D, Pergoli L, Dalla Valle E, Barretta F, Cortini F, et al. DNA methylation in repetitive elements and Alzheimer disease. Brain Behav Immun. 2011;25(6):1078-83.

  3. Hernandez HG, Mahecha MF, Mejia A, Arboleda H, Forero DA. Global long interspersed nuclear element 1 DNA methylation in a Colombian sample of patients with late-onset Alzheimer's disease. Am J Alzheimers Dis Other Demen. 2014;29(1):50-3.

  4. Protasova MS, Gusev FE, Grigorenko AP, Kuznetsova IL, Rogaev EI, Andreeva TV. Quantitative Analysis of L1-Retrotransposons in Alzheimer's Disease and Aging. Biochemistry (Mosc). 2017;82(8):962-71.

  5. Guo C, Jeong HH, Hsieh YC, Klein HU, Bennett DA, De Jager PL, et al. Tau Activates Transposable Elements in Alzheimer's Disease. Cell Rep. 2018;23(10):2874-80.

  6. Verheijen BM, Vermulst M, van Leeuwen FW. Somatic mutations in neurons during aging and neurodegeneration. Acta Neuropathol. 2018;135(6):811-26.

  7. Li W, Prazak L, Chatterjee N, Gruninger S, Krug L, Theodorou D, et al. Activation of transposable elements during aging and neuronal decline in Drosophila. Nat Neurosci. 2013;16(5):529-31.

  8. Kemp JR, Longworth MS. Crossing the LINE Toward Genomic Instability: LINE-1 Retrotransposition in Cancer. Front Chem. 2015;3:68.

  9. Kazazian HH, Jr., Moran JV. Mobile DNA in Health and Disease. N Engl J Med. 2017;377(4):361-70.

  10. Belancio VP, Roy-Engel AM, Deininger PL. All y'all need to know 'bout retroelements in cancer. Semin Cancer Biol. 2010;20(4):200-10.

  11. Alves G, Tatro A, Fanning T. Differential methylation of human LINE-1 retrotransposons in malignant cells. Gene. 1996;176(1-2):39-44.

  12. Scott EC, Devine SE. The Role of Somatic L1 Retrotransposition in Human Cancers. Viruses. 2017;9(6).

  13. Rangwala SH, Kazazian HH, Jr. The L1 retrotransposition assay: a retrospective and toolkit. Methods. 2009;49(3):219-26.

  14. Kopera HC, Larson P A, Moldovan JB, Richardson SR, Liu Y , Moran JV . LINE-1 Cultured Cell Retrotransposition Assay. Methods Mol Biol. 2016;1400:139-56.

  15. Moran JV, Holmes SE, Naas TP, DeBerardinis RJ, Boeke JD, Kazazian HH, Jr. High frequency retrotransposition in cultured mammalian cells. Cell. 1996;87(5):917-27.

  16. Ostertag EM, Prak ET, DeBerardinis RJ, Moran JV, Kazazian HH, Jr. Determination of L1 retrotransposition kinetics in cultured cells. Nucleic Acids Res. 2000;28(6):1418-23.

  17. Del Re B, Marcantonio P, Capri M, Giorgi G. Evaluation of LINE-1 mobility in neuroblastoma cells by in vitro retrotransposition reporter assay: FACS analysis can detect only the tip of the iceberg of the inserted L1 elements. Exp Cell Res. 2010;316(20):3358-67.

  18. Vandekerckhove L, Christ F, Van Maele B, De Rijck J, Gijsbers R, Van den Haute C, et al. Transient and stable knockdown of the integrase cofactor LEDGF/p75 reveals its role in the replication cycle of human immunodeficiency virus. J Virol. 2006;80(4):1886-96.

  19. Osorio L, Gijsbers R, Oliveras-Salva M, Michiels A, Debyser Z, Van den Haute C, et al. Viral vectors expressing a single microRNA-based short-hairpin RNA result in potent gene silencing in vitro and in vivo. J Biotechnol. 2014;169:71-81.

  20. Mangeot PE, Duperrier K, Negre D, Boson B, Rigal D, Cosset FL, et al. High levels of transduction of human dendritic cells with optimized SIV vectors. Mol Ther. 2002;5(3):283- 90.

  1. Geraerts M, Michiels M, Baekelandt V, Debyser Z, Gijsbers R. Upscaling of lentiviral vector production by tangential flow filtration. J Gene Med. 2005;7(10):1299-310.

  2. Naldini L, Blomer U, Gage FH, Trono D, Verma IM. Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci U S A. 1996;93(21):11382-8.

  3. Vranckx LS, Demeulemeester J, Saleh S, Boll A, Vansant G, Schrijvers R, et al. LEDGIN- mediated Inhibition of Integrase-LEDGF/p75 Interaction Reduces Reactivation of Residual Latent HIV. EBioMedicine. 2016;8:248-64.

  4. Bueno C, Tabares-Seisdedos R, Moraleda JM, Martinez S. Rett Syndrome Mutant Neural Cells Lacks MeCP2 Immunoreactive Bands. PLoS One. 2016;11(4):e0153262.

  5. Schwahn U, Lenzner S, Dong J, Feil S, Hinzmann B, van Duijnhoven G, et al. Positional cloning of the gene for X-linked retinitis pigmentosa 2. Nat Genet. 1998;19(4):327-32.

  6. Metzner M, Jack HM, Wabl M. LINE-1 retroelements complexed and inhibited by activation

    induced cytidine deaminase. PLoS One. 2012;7(11):e49358.

  7. Cook PR, Tabor GT. Deciphering fact from artifact when using reporter assays to investigate

    the roles of host factors on L1 retrotransposition. Mob DNA. 2016;7:23.

  8. Leoh LS, van Heertum B, De Rijck J, Filippova M, Rios-Colon L, Basu A, et al. The stress oncoprotein LEDGF/p75 interacts with the methyl CpG binding protein MeCP2 and influences

    its transcriptional activity. Mol Cancer Res. 2012;10(3):378-91.

  9. MacLennan M, Garcia-Canadas M, Reichmann J, Khazina E, Wagner G, Playfoot CJ, et al.

    Mobilization of LINE-1 retrotransposons is restricted by Tex19.1 in mouse embryonic stem

    cells. Elife. 2017;6.

  10. Streva VA, Faber ZJ, Deininger PL. LINE-1 and Alu retrotransposition exhibit clonal variation.

    Mob DNA. 2013;4(1):16.

  11. Swergold GD. Identification, characterization, and cell specificity of a human LINE-1

    promoter. Mol Cell Biol. 1990;10(12):6718-29.

  12. Leibold DM, Swergold GD, Singer MF, Thayer RE, Dombroski BA, Fanning TG. Translation

    of LINE-1 DNA elements in vitro and in human cells. Proc Natl Acad Sci U S A.

    1990;87(18):6990-4.

  13. Brouha B, Meischl C, Ostertag E, de Boer M, Zhang Y, Neijens H, et al. Evidence consistent

    with human L1 retrotransposition in maternal meiosis I. Am J Hum Genet. 2002;71(2):327-36.

  14. Garcia-Perez JL, Morell M, Scheys JO, Kulpa DA, Morell S, Carter CC, et al. Epigenetic silencing of engineered L1 retrotransposition events in human embryonic carcinoma cells.

    Nature. 2010;466(7307):769-73.

  15. Ge H, Si Y, Roeder RG. Isolation of cDNAs encoding novel transcription coactivators p52 and

    p75 reveals an alternate regulatory mechanism of transcriptional activation. EMBO J.

    1998;17(22):6723-9.

  16. Turlure F, Maertens G, Rahman S, Cherepanov P, Engelman A. A tripartite DNA-binding

    element, comprised of the nuclear localization signal and two AT-hook motifs, mediates the

    association of LEDGF/p75 with chromatin in vivo. Nucleic Acids Res. 2006;34(5):1653-65.

  17. Li R, Dong Q, Yuan X, Zeng X, Gao Y, Chiao C, et al. Misregulation of Alternative Splicing

    in a Mouse Model of Rett Syndrome. PLoS Genet. 2016;12(6):e1006129.

  18. Cherepanov P, Maertens G, Proost P, Devreese B, Van Beeumen J, Engelborghs Y, et al. HIV- 1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J

    Biol Chem. 2003;278(1):372-81.

  19. Weichenrieder O, Repanas K, Perrakis A. Crystal structure of the targeting endonuclease of the

    human LINE-1 retrotransposon. Structure. 2004;12(6):975-86.

  1. Repanas K, Zingler N, Layer LE, Schumann GG, Perrakis A, Weichenrieder O. Determinants for DNA target structure selectivity of the human LINE-1 retrotransposon endonuclease. Nucleic Acids Res. 2007;35(14):4914-26.

  2. Sultana T, van Essen D, Siol O, Bailly-Bechet M, Philippe C, Zine El Aabidine A, et al. The Landscape of L1 Retrotransposons in the Human Genome Is Shaped by Pre-insertion Sequence Biases and Post-insertion Selection. Mol Cell. 2019;74(3):555-70 e7.

  3. Flasch DA, Macia A, Sanchez L, Ljungman M, Heras SR, Garcia-Perez JL, et al. Genome-wide de novo L1 Retrotransposition Connects Endonuclease Activity with Replication. Cell. 2019;177(4):837-51 e28.

  4. Daugaard M, Baude A, Fugger K, Povlsen LK, Beck H, Sorensen CS, et al. LEDGF (p75) promotes DNA-end resection and homologous recombination. Nat Struct Mol Biol. 2012;19(8):803-10.

  5. Katz RA, Greger JG, Skalka AM. Effects of cell cycle status on early events in retroviral replication. J Cell Biochem. 2005;94(5):880-9.

  6. Sinclair A, Yarranton S, Schelcher C. DNA-damage response pathways triggered by viral replication. Expert Rev Mol Med. 2006;8(5):1-11.

  7. Skalka AM, Katz RA. Retroviral DNA integration and the DNA damage response. Cell Death Differ. 2005;12 Suppl 1:971-8.

  8. Mita P, Sun X, Fenyo D, Kahler DJ, Li D, Agmon N, et al. BRCA1 and S phase DNA repair pathways restrict LINE-1 retrotransposition in human cells. Nat Struct Mol Biol. 2020;27(2):179-91.

  9. An W, Dai L, Niewiadomska AM, Yetil A, O'Donnell KA, Han JS, et al. Characterization of a synthetic human LINE-1 retrotransposon ORFeus-Hs. Mob DNA. 2011;2(1):2.

Universiteit of Hogeschool
Master of Biomedical Sciences
Publicatiejaar
2020
Promotor(en)
Prof. Zeger Debyser
Kernwoorden
Share this on: