Interplay between RNASEH2 and MOV10 controls LINE-1 retrotransposition
Jongsu Choi, Sung-Yeon Hwang, Kwangseog Ahn, Jongsu Choi, Sung-Yeon Hwang, Kwangseog Ahn
Abstract
Long interspersed nuclear element 1 is an autonomous non-long terminal repeat retrotransposon that comprises ∼17% of the human genome. Its spontaneous retrotransposition and the accumulation of heritable L1 insertions can potentially result in genome instability and sporadic disorders. Moloney leukemia virus 10 homolog (MOV10), a putative RNA helicase, has been implicated in inhibiting L1 replication, although its underlying mechanism of action remains obscure. Moreover, the physiological relevance of MOV10-mediated L1 regulation in human disease has not yet been examined. Using a proteomic approach, we identified RNASEH2 as a binding partner of MOV10. We show that MOV10 interacts with RNASEH2, and their interplay is crucial for restricting L1 retrotransposition. RNASEH2 and MOV10 co-localize in the nucleus, and RNASEH2 binds to L1 RNAs in a MOV10-dependent manner. Small hairpin RNA-mediated depletion of either RNASEH2A or MOV10 results in an accumulation of L1-specific RNA-DNA hybrids, suggesting they contribute to prevent formation of vital L1 heteroduplexes during retrotransposition. Furthermore, we show that RNASEH2-MOV10-mediated L1 restriction downregulates expression of the rheumatoid arthritis-associated inflammatory cytokines and matrix-degrading proteinases in synovial cells, implicating a potential causal relationship between them and disease development in terms of disease predisposition.
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References
- Lander E.S., Linton L.M., Birren B., Nusbaum C., Zody M.C., Baldwin J., Devon K., Dewar K., Doyle M., FitzHugh W. et al. . Initial sequencing and analysis of the human genome. Nature. 2001; 409:860–921.
- Luan D.D., Korman M.H., Jakubczak J.L., Eickbush T.H.. Reverse transcription of R2Bm RNA is primed by a nick at the chromosomal target site: a mechanism for non-LTR retrotransposition. Cell. 1993; 72:595–605.
- Moran J.V., Holmes S.E., Naas T.P., DeBerardinis R.J., Boeke J.D., Kazazian H.H. Jr. High frequency retrotransposition in cultured mammalian cells. Cell. 1996; 87:917–927.
- Hancks D.C., Kazazian H.H. Jr. Active human retrotransposons: variation and disease. Curr. Opin. Genet. Dev. 2012; 22:191–203.
- Miki Y., Nishisho I., Horii A., Miyoshi Y., Utsunomiya J., Kinzler K.W., Vogelstein B., Nakamura Y.. Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res. 1992; 52:643–645.
- Kazazian H.H. Jr, Moran J.V.. The impact of L1 retrotransposons on the human genome. Nat. Genet. 1998; 19:19–24.
- Gasior S.L., Wakeman T.P., Xu B., Deininger P.L.. The human LINE-1 retrotransposon creates DNA double-strand breaks. J. Mol. Biol. 2006; 357:1383–1393.
- Volkman H.E., Stetson D.B.. The enemy within: endogenous retroelements and autoimmune disease. Nat. Immunol. 2014; 15:415–422.
- Hamann L., Jensen K., Harbers K.. Consecutive inactivation of both alleles of the gb110 gene has no effect on the proliferation and differentiation of mouse embryonic stem cells. Gene. 1993; 126:279–284.
- Gregersen L.H., Schueler M., Munschauer M., Mastrobuoni G., Chen W., Kempa S., Dieterich C., Landthaler M.. MOV10 Is a 5′ to 3′ RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3′ UTRs. Mol. Cell. 2014; 54:573–585.
- Burdick R., Smith J.L., Chaipan C., Friew Y., Chen J., Venkatachari N.J., Delviks-Frankenberry K.A., Hu W.S., Pathak V.K.. P body-associated protein Mov10 inhibits HIV-1 replication at multiple stages. J. Virol. 2010; 84:10241–10253.
- Wang X., Han Y., Dang Y., Fu W., Zhou T., Ptak R.G., Zheng Y.H.. Moloney leukemia virus 10 (MOV10) protein inhibits retrovirus replication. J. Biol. Chem. 2010; 285:14346–14355.
- Arjan-Odedra S., Swanson C.M., Sherer N.M., Wolinsky S.M., Malim M.H.. Endogenous MOV10 inhibits the retrotransposition of endogenous retroelements but not the replication of exogenous retroviruses. Retrovirology. 2012; 9:53.
- Goodier J.L., Cheung L.E., Kazazian H.H. Jr. MOV10 RNA helicase is a potent inhibitor of retrotransposition in cells. PLoS Genet. 2012; 8:e1002941.
- Li X., Zhang J., Jia R., Cheng V., Xu X., Qiao W., Guo F., Liang C., Cen S.. The MOV10 helicase inhibits LINE-1 mobility. J. Biol. Chem. 2013; 288:21148–21160.
- Moldovan J.B., Moran J.V.. The zinc-finger antiviral protein ZAP inhibits LINE and alu retrotransposition. PLoS Genet. 2015; 11:e1005121.
- Skariah G., Seimetz J., Norsworthy M., Lannom M.C., Kenny P.J., Elrakhawy M., Forsthoefel C., Drnevich J., Kalsotra A., Ceman S.. Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain. BMC Biol. 2017; 15:54.
- Malik H.S., Eickbush T.H.. Phylogenetic analysis of ribonuclease H domains suggests a late, chimeric origin of LTR retrotransposable elements and retroviruses. Genome Res. 2001; 11:1187–1197.
- Malik H.S., Henikoff S., Eickbush T.H.. Poised for contagion: evolutionary origins of the infectious abilities of invertebrate retroviruses. Genome Res. 2000; 10:1307–1318.
- Kenny P.J., Zhou H., Kim M., Skariah G., Khetani R.S., Drnevich J., Arcila M.L., Kosik K.S., Ceman S.. MOV10 and FMRP regulate AGO2 association with microRNA recognition elements. Cell Rep. 2014; 9:1729–1741.
- Furtak V., Mulky A., Rawlings S.A., Kozhaya L., Lee K., Kewalramani V.N., Unutmaz D.. Perturbation of the P-body component Mov10 inhibits HIV-1 infectivity. PLoS One. 2010; 5:e9081.
- El Messaoudi-Aubert S., Nicholls J., Maertens G.N., Brookes S., Bernstein E., Peters G.. Role for the MOV10 RNA helicase in polycomb-mediated repression of the INK4a tumor suppressor. Nat. Struct. Mol. Biol. 2010; 17:862–868.
- Jeong H.S., Backlund P.S., Chen H.C., Karavanov A.A., Crouch R.J.. RNase H2 of Saccharomyces cerevisiae is a complex of three proteins. Nucleic Acids Res. 2004; 32:407–414.
- Rychlik M.P., Chon H., Cerritelli S.M., Klimek P., Crouch R.J., Nowotny M.. Crystal structures of RNase H2 in complex with nucleic acid reveal the mechanism of RNA-DNA junction recognition and cleavage. Mol. Cell. 2010; 40:658–670.
- Sparks J.L., Chon H., Cerritelli S.M., Kunkel T.A., Johansson E., Crouch R.J., Burgers P.M.. RNase H2-initiated ribonucleotide excision repair. Mol. Cell. 2012; 47:980–986.
- Chon H., Sparks J.L., Rychlik M., Nowotny M., Burgers P.M., Crouch R.J., Cerritelli S.M.. RNase H2 roles in genome integrity revealed by unlinking its activities. Nucleic Acids Res. 2013; 41:3130–3143.
- Genovesio A., Kwon Y.J., Windisch M.P., Kim N.Y., Choi S.Y., Kim H.C., Jung S., Mammano F., Perrin V., Boese A.S. et al. . Automated genome-wide visual profiling of cellular proteins involved in HIV infection. J. Biomol. Screen. 2011; 16:945–958.
- Kennedy E.M., Gavegnano C., Nguyen L., Slater R., Lucas A., Fromentin E., Schinazi R.F., Kim B.. Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages. J. Biol. Chem. 2010; 285:39380–39391.
- Ayinde D., Casartelli N., Schwartz O.. Restricting HIV the SAMHD1 way: through nucleotide starvation. Nat. Rev. Microbiol. 2012; 10:675–680.
- Crow Y.J., Leitch A., Hayward B.E., Garner A., Parmar R., Griffith E., Ali M., Semple C., Aicardi J., Babul-Hirji R. et al. . Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat. Genet. 2006; 38:910–916.
- Perrino F.W., Harvey S., Shaban N.M., Hollis T.. RNaseH2 mutants that cause Aicardi-Goutieres syndrome are active nucleases. J. Mol. Med. (Berl). 2009; 87:25–30.
- Lim Y.W., Sanz L.A., Xu X., Hartono S.R., Chedin F.. Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi-Goutieres syndrome. Elife. 2015; 4:e08007.
- Pokatayev V., Hasin N., Chon H., Cerritelli S.M., Sakhuja K., Ward J.M., Morris H.D., Yan N., Crouch R.J.. RNase H2 catalytic core Aicardi-Goutieres syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J. Exp. Med. 2016; 213:329–336.
- Bartsch K., Knittler K., Borowski C., Rudnik S., Damme M., Aden K., Spehlmann M.E., Frey N., Saftig P., Chalaris A. et al. . Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy. Hum. Mol. Genet. 2017; 26:3960–3972.
- Meister G., Landthaler M., Peters L., Chen P.Y., Urlaub H., Luhrmann R., Tuschl T.. Identification of novel argonaute-associated proteins. Curr. Biol. 2005; 15:2149–2155.
- Kroutter E.N., Belancio V.P., Wagstaff B.J., Roy-Engel A.M.. The RNA polymerase dictates ORF1 requirement and timing of LINE and SINE retrotransposition. PLoS Genet. 2009; 5:e1000458.
- Xie Y., Rosser J.M., Thompson T.L., Boeke J.D., An W.. Characterization of L1 retrotransposition with high-throughput dual-luciferase assays. Nucleic Acids Res. 2011; 39:e16.
- Doucet A.J., Hulme A.E., Sahinovic E., Kulpa D.A., Moldovan J.B., Kopera H.C., Athanikar J.N., Hasnaoui M., Bucheton A., Moran J.V. et al. . Characterization of LINE-1 ribonucleoprotein particles. PLoS Genet. 2010; 6:e1001150.
- Fusco D., Accornero N., Lavoie B., Shenoy S.M., Blanchard J.M., Singer R.H., Bertrand E.. Single mRNA molecules demonstrate probabilistic movement in living mammalian cells. Curr. Biol. 2003; 13:161–167.
- Bhatia V., Barroso S.I., Garcia-Rubio M.L., Tumini E., Herrera-Moyano E., Aguilera A.. BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature. 2014; 511:362–365.
- Geissmann Q. OpenCFU, a new free and open-source software to count cell colonies and other circular objects. PLoS One. 2013; 8:e54072.
- Ginno P.A., Lott P.L., Christensen H.C., Korf I., Chedin F.. R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Mol. Cell. 2012; 45:814–825.
- Taylor M.S., LaCava J., Mita P., Molloy K.R., Huang C.R., Li D., Adney E.M., Jiang H., Burns K.H., Chait B.T. et al. . Affinity proteomics reveals human host factors implicated in discrete stages of LINE-1 retrotransposition. Cell. 2013; 155:1034–1048.
- Goodier J.L., Cheung L.E., Kazazian H.H. Jr. Mapping the LINE1 ORF1 protein interactome reveals associated inhibitors of human retrotransposition. Nucleic Acids Res. 2013; 41:7401–7419.
- Kind B., Muster B., Staroske W., Herce H.D., Sachse R., Rapp A., Schmidt F., Koss S., Cardoso M.C., Lee-Kirsch M.A.. Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutieres syndrome. Hum. Mol. Genet. 2014; 23:5950–5960.
- Boguslawski S.J., Smith D.E., Michalak M.A., Mickelson K.E., Yehle C.O., Patterson W.L., Carrico R.J.. Characterization of monoclonal antibody to DNA.RNA and its application to immunodetection of hybrids. J. Immunol. Methods. 1986; 89:123–130.
- Brown T.A., Tkachuk A.N., Clayton D.A.. Native R-loops persist throughout the mouse mitochondrial DNA genome. J. Biol. Chem. 2008; 283:36743–36751.
- Zhang Z.Z., Pannunzio N.R., Hsieh C.L., Yu K., Lieber M.R.. Complexities due to single-stranded RNA during antibody detection of genomic rna:dna hybrids. BMC Res. Notes. 2015; 8:127.
- Santos-Pereira J.M., Aguilera A.. R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 2015; 16:583–597.
- Yamazaki T., Yokoyama T., Akatsu H., Tukiyama T., Tokiwa T.. Phenotypic characterization of a human synovial sarcoma cell line, SW982, and its response to dexamethasone. In Vitro Cell Dev. Biol. Anim. 2003; 39:337–339.
- Lu C., Luo Z., Jager S., Krogan N.J., Peterlin B.M.. Moloney leukemia virus type 10 inhibits reverse transcription and retrotransposition of intracisternal a particles. J. Virol. 2012; 86:10517–10523.
- Doucet A.J., Wilusz J.E., Miyoshi T., Liu Y., Moran J.V.. A 3′ Poly(A) tract is required for LINE-1 retrotransposition. Mol. Cell. 2015; 60:728–741.
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