{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:01:47Z","timestamp":1790949707673,"version":"4.1.0"},"reference-count":73,"publisher":"National Academy of Sciences","issue":"12","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2017,3,21]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    Spinal muscular atrophy is the leading monogenic cause of infant mortality and is caused by homozygous loss of the survival of motor neuron 1 (\n                    <jats:italic>SMN1<\/jats:italic>\n                    ) gene. We investigated global transcriptome changes in the spinal cord of inducible SMA mice. SMN depletion caused widespread retention of introns with weak splice sites or belonging to the minor (U12) class. In addition, DNA double strand breaks accumulated in the spinal cord of SMA mice and in human SMA cell culture models. DNA damage was partially rescued by suppressing the formation of R-loops, which accumulated over retained introns. We propose that instead of single gene effects, pervasive splicing defects caused by severe SMN deficiency trigger a global DNA damage and stress response, thus compromising motor neuron survival.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1613181114","type":"journal-article","created":{"date-parts":[[2017,3,7]],"date-time":"2017-03-07T21:10:33Z","timestamp":1488921033000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":127,"title":["SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage"],"prefix":"10.1073","volume":"114","author":[{"given":"Mohini","family":"Jangi","sequence":"first","affiliation":[{"name":"Computational Biology &amp; Genomics, Biogen, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Fleet","sequence":"additional","affiliation":[{"name":"Computational Biology &amp; Genomics, Biogen, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Cullen","sequence":"additional","affiliation":[{"name":"Computational Biology &amp; Genomics, Biogen, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shipra V.","family":"Gupta","sequence":"additional","affiliation":[{"name":"Computational Biology &amp; Genomics, Biogen, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shila","family":"Mekhoubad","sequence":"additional","affiliation":[{"name":"Stem Cell Research, Biogen, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Chiao","sequence":"additional","affiliation":[{"name":"Stem Cell Research, Biogen, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norm","family":"Allaire","sequence":"additional","affiliation":[{"name":"Computational Biology &amp; Genomics, Biogen, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Frank","family":"Bennett","sequence":"additional","affiliation":[{"name":"Neuroscience Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA 92008;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Rigo","sequence":"additional","affiliation":[{"name":"Neuroscience Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA 92008;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian R.","family":"Krainer","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A.","family":"Hurt","sequence":"additional","affiliation":[{"name":"Computational Biology &amp; Genomics, Biogen, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Carulli","sequence":"additional","affiliation":[{"name":"Computational Biology &amp; Genomics, Biogen, Cambridge, MA 02142;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Staropoli","sequence":"additional","affiliation":[{"name":"Rare Disease, Biogen, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2017,3,7]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1055\/s-2001-15264","article-title":"Spinal muscular atrophy","volume":"21","author":"Talbot K","year":"2001","unstructured":"K Talbot, KE Davies, Spinal muscular atrophy. Semin Neurol 21, 189\u2013197 (2001).","journal-title":"Semin Neurol"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S0887-8994(97)00227-0","article-title":"Treatment of type I spinal muscular atrophy with noninvasive ventilation and gastrostomy feeding","volume":"18","author":"Birnkrant DJ","year":"1998","unstructured":"DJ Birnkrant, JF Pope, JE Martin, AH Repucci, RM Eiben, Treatment of type I spinal muscular atrophy with noninvasive ventilation and gastrostomy feeding. Pediatr Neurol 18, 407\u2013410 (1998).","journal-title":"Pediatr Neurol"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1086\/513886","article-title":"Genomic variation and gene conversion in spinal muscular atrophy: Implications for disease process and clinical phenotype","volume":"61","author":"Campbell L","year":"1997","unstructured":"L Campbell, A Potter, J Ignatius, V Dubowitz, K Davies, Genomic variation and gene conversion in spinal muscular atrophy: Implications for disease process and clinical phenotype. Am J Hum Genet 61, 40\u201350 (1997).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0092-8674(95)90460-3","article-title":"Identification and characterization of a spinal muscular atrophy-determining gene","volume":"80","author":"Lefebvre S","year":"1995","unstructured":"S Lefebvre, , Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155\u2013165 (1995).","journal-title":"Cell"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1128\/MCB.01262-08","article-title":"Regulation of SMN protein stability","volume":"29","author":"Burnett BG","year":"2009","unstructured":"BG Burnett, , Regulation of SMN protein stability. Mol Cell Biol 29, 1107\u20131115 (2009).","journal-title":"Mol Cell Biol"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.ygeno.2015.01.007","article-title":"Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7","volume":"105","author":"Staropoli JF","year":"2015","unstructured":"JF Staropoli, , Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7. Genomics 105, 220\u2013228 (2015).","journal-title":"Genomics"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1002\/emmm.201302567","article-title":"Pathological impact of SMN2 mis-splicing in adult SMA mice","volume":"5","author":"Sahashi K","year":"2013","unstructured":"K Sahashi, , Pathological impact of SMN2 mis-splicing in adult SMA mice. EMBO Mol Med 5, 1586\u20131601 (2013).","journal-title":"EMBO Mol Med"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1093\/hmg\/6.8.1205","article-title":"The survival motor neuron protein in spinal muscular atrophy","volume":"6","author":"Coovert DD","year":"1997","unstructured":"DD Coovert, , The survival motor neuron protein in spinal muscular atrophy. Hum Mol Genet 6, 1205\u20131214 (1997).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/ng0797-265","article-title":"Correlation between severity and SMN protein level in spinal muscular atrophy","volume":"16","author":"Lefebvre S","year":"1997","unstructured":"S Lefebvre, , Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 16, 265\u2013269 (1997).","journal-title":"Nat Genet"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0002-9440(10)65578-2","article-title":"Cell-specific survival motor neuron gene expression during human development of the central nervous system: Implications for the pathogenesis of spinal muscular atrophy","volume":"153","author":"Tizzano EF","year":"1998","unstructured":"EF Tizzano, C Cabot, M Baiget, Cell-specific survival motor neuron gene expression during human development of the central nervous system: Implications for the pathogenesis of spinal muscular atrophy. Am J Pathol 153, 355\u2013361 (1998).","journal-title":"Am J Pathol"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1016\/j.cell.2009.02.009","article-title":"The spliceosome: Design principles of a dynamic RNP machine","volume":"136","author":"Wahl MC","year":"2009","unstructured":"MC Wahl, CL Will, R L\u00fchrmann, The spliceosome: Design principles of a dynamic RNP machine. Cell 136, 701\u2013718 (2009).","journal-title":"Cell"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nrn2670","article-title":"Spinal muscular atrophy: Why do low levels of survival motor neuron protein make motor neurons sick?","volume":"10","author":"Burghes AH","year":"2009","unstructured":"AH Burghes, CE Beattie, Spinal muscular atrophy: Why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci 10, 597\u2013609 (2009).","journal-title":"Nat Rev Neurosci"},{"key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/sj.embor.7400941","article-title":"Chaperoning ribonucleoprotein biogenesis in health and disease","volume":"8","author":"Pellizzoni L","year":"2007","unstructured":"L Pellizzoni, Chaperoning ribonucleoprotein biogenesis in health and disease. EMBO Rep 8, 340\u2013345 (2007).","journal-title":"EMBO Rep"},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.semcdb.2014.04.026","article-title":"SMN control of RNP assembly: From post-transcriptional gene regulation to motor neuron disease","volume":"32","author":"Li DK","year":"2014","unstructured":"DK Li, S Tisdale, F Lotti, L Pellizzoni, SMN control of RNP assembly: From post-transcriptional gene regulation to motor neuron disease. Semin Cell Dev Biol 32, 22\u201329 (2014).","journal-title":"Semin Cell Dev Biol"},{"key":"e_1_3_4_15_2","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1126\/science.1074962","article-title":"Essential role for the SMN complex in the specificity of snRNP assembly","volume":"298","author":"Pellizzoni L","year":"2002","unstructured":"L Pellizzoni, J Yong, G Dreyfuss, Essential role for the SMN complex in the specificity of snRNP assembly. Science 298, 1775\u20131779 (2002).","journal-title":"Science"},{"key":"e_1_3_4_16_2","doi-asserted-by":"crossref","first-page":"3914","DOI":"10.1523\/JNEUROSCI.3631-10.2011","article-title":"The survival of motor neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons","volume":"31","author":"Fallini C","year":"2011","unstructured":"C Fallini, , The survival of motor neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons. J Neurosci 31, 3914\u20133925 (2011).","journal-title":"J Neurosci"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"6627","DOI":"10.1523\/JNEUROSCI.23-16-06627.2003","article-title":"Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization","volume":"23","author":"Zhang HL","year":"2003","unstructured":"HL Zhang, , Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization. J Neurosci 23, 6627\u20136637 (2003).","journal-title":"J Neurosci"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.brainres.2012.01.044","article-title":"Spinal muscular atrophy: The role of SMN in axonal mRNA regulation","volume":"1462","author":"Fallini C","year":"2012","unstructured":"C Fallini, GJ Bassell, W Rossoll, Spinal muscular atrophy: The role of SMN in axonal mRNA regulation. Brain Res 1462, 81\u201392 (2012).","journal-title":"Brain Res"},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.cell.2008.03.031","article-title":"SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing","volume":"133","author":"Zhang Z","year":"2008","unstructured":"Z Zhang, , SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell 133, 585\u2013600 (2008).","journal-title":"Cell"},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","first-page":"19348","DOI":"10.1073\/pnas.1319280110","article-title":"Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy","volume":"110","author":"Zhang Z","year":"2013","unstructured":"Z Zhang, , Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy. Proc Natl Acad Sci USA 110, 19348\u201319353 (2013).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_21_2","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1261\/rna.038919.113","article-title":"Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes","volume":"19","author":"Garcia EL","year":"2013","unstructured":"EL Garcia, Z Lu, MP Meers, K Praveen, AG Matera, Developmental arrest of Drosophila survival motor neuron (Smn) mutants accounts for differences in expression of minor intron-containing genes. RNA 19, 1510\u20131516 (2013).","journal-title":"RNA"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.celrep.2012.05.014","article-title":"A Drosophila model of spinal muscular atrophy uncouples snRNP biogenesis functions of survival motor neuron from locomotion and viability defects","volume":"1","author":"Praveen K","year":"2012","unstructured":"K Praveen, Y Wen, AG Matera, A Drosophila model of spinal muscular atrophy uncouples snRNP biogenesis functions of survival motor neuron from locomotion and viability defects. Cell Reports 1, 624\u2013631 (2012).","journal-title":"Cell Reports"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"e1000773","DOI":"10.1371\/journal.pgen.1000773","article-title":"Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy","volume":"5","author":"B\u00e4umer D","year":"2009","unstructured":"D B\u00e4umer, , Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy. PLoS Genet 5, e1000773 (2009).","journal-title":"PLoS Genet"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"3316","DOI":"10.1172\/JCI35432","article-title":"Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy","volume":"118","author":"Corti S","year":"2008","unstructured":"S Corti, , Neural stem cell transplantation can ameliorate the phenotype of a mouse model of spinal muscular atrophy. J Clin Invest 118, 3316\u20133330 (2008).","journal-title":"J Clin Invest"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1128\/MCB.06077-11","article-title":"A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy","volume":"32","author":"Ruggiu M","year":"2012","unstructured":"M Ruggiu, , A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy. Mol Cell Biol 32, 126\u2013138 (2012).","journal-title":"Mol Cell Biol"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1093\/hmg\/ddq500","article-title":"HuD interacts with survival motor neuron protein and can rescue spinal muscular atrophy-like neuronal defects","volume":"20","author":"Hubers L","year":"2011","unstructured":"L Hubers, , HuD interacts with survival motor neuron protein and can rescue spinal muscular atrophy-like neuronal defects. Hum Mol Genet 20, 553\u2013579 (2011).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1093\/hmg\/ddm327","article-title":"KH-type splicing regulatory protein interacts with survival motor neuron protein and is misregulated in spinal muscular atrophy","volume":"17","author":"Tadesse H","year":"2008","unstructured":"H Tadesse, J Desch\u00eanes-Furry, S Boisvenue, J C\u00f4t\u00e9, KH-type splicing regulatory protein interacts with survival motor neuron protein and is misregulated in spinal muscular atrophy. Hum Mol Genet 17, 506\u2013524 (2008).","journal-title":"Hum Mol Genet"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/nature16469","article-title":"SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination","volume":"529","author":"Zhao DY","year":"2016","unstructured":"DY Zhao, , SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination. Nature 529, 48\u201353 (2016).","journal-title":"Nature"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"E5593","DOI":"10.1073\/pnas.1419161111","article-title":"rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data","volume":"111","author":"Shen S","year":"2014","unstructured":"S Shen, , rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Proc Natl Acad Sci USA 111, E5593\u2013E5601 (2014).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"D110","DOI":"10.1093\/nar\/gkl796","article-title":"U12DB: A database of orthologous U12-type spliceosomal introns","volume":"35","author":"Alioto TS","year":"2007","unstructured":"TS Alioto, U12DB: A database of orthologous U12-type spliceosomal introns. Nucleic Acids Res 35, D110\u2013D115 (2007).","journal-title":"Nucleic Acids Res"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/nmeth.1528","article-title":"Analysis and design of RNA sequencing experiments for identifying isoform regulation","volume":"7","author":"Katz Y","year":"2010","unstructured":"Y Katz, ET Wang, EM Airoldi, CB Burge, Analysis and design of RNA sequencing experiments for identifying isoform regulation. Nat Methods 7, 1009\u20131015 (2010).","journal-title":"Nat Methods"},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1101\/gr.177790.114","article-title":"Widespread intron retention in mammals functionally tunes transcriptomes","volume":"24","author":"Braunschweig U","year":"2014","unstructured":"U Braunschweig, , Widespread intron retention in mammals functionally tunes transcriptomes. Genome Res 24, 1774\u20131786 (2014).","journal-title":"Genome Res"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1016\/j.celrep.2014.04.044","article-title":"Widespread inhibition of posttranscriptional splicing shapes the cellular transcriptome following heat shock","volume":"7","author":"Shalgi R","year":"2014","unstructured":"R Shalgi, JA Hurt, S Lindquist, CB Burge, Widespread inhibition of posttranscriptional splicing shapes the cellular transcriptome following heat shock. Cell Reports 7, 1362\u20131370 (2014).","journal-title":"Cell Reports"},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.cell.2013.06.052","article-title":"Orchestrated intron retention regulates normal granulocyte differentiation","volume":"154","author":"Wong JJ","year":"2013","unstructured":"JJ Wong, , Orchestrated intron retention regulates normal granulocyte differentiation. Cell 154, 583\u2013595 (2013).","journal-title":"Cell"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1101\/gad.188037.112","article-title":"Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention","volume":"26","author":"Yap K","year":"2012","unstructured":"K Yap, ZQ Lim, P Khandelia, B Friedman, EV Makeyev, Coordinated regulation of neuronal mRNA steady-state levels through developmentally controlled intron retention. Genes Dev 26, 1209\u20131223 (2012).","journal-title":"Genes Dev"},{"key":"e_1_3_4_36_2","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/1066527041410418","article-title":"Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals","volume":"11","author":"Yeo G","year":"2004","unstructured":"G Yeo, CB Burge, Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11, 377\u2013394 (2004).","journal-title":"J Comput Biol"},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1083\/jcb.143.2.457","article-title":"Cyclin-dependent kinases participate in death of neurons evoked by DNA-damaging agents","volume":"143","author":"Park DS","year":"1998","unstructured":"DS Park, , Cyclin-dependent kinases participate in death of neurons evoked by DNA-damaging agents. J Cell Biol 143, 457\u2013467 (1998).","journal-title":"J Cell Biol"},{"key":"e_1_3_4_38_2","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.molcel.2009.06.021","article-title":"A genome-wide siRNA screen reveals diverse cellular processes and pathways that mediate genome stability","volume":"35","author":"Paulsen RD","year":"2009","unstructured":"RD Paulsen, , A genome-wide siRNA screen reveals diverse cellular processes and pathways that mediate genome stability. Mol Cell 35, 228\u2013239 (2009).","journal-title":"Mol Cell"},{"key":"e_1_3_4_39_2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.molcel.2012.04.009","article-title":"R loops: From transcription byproducts to threats to genome stability","volume":"46","author":"Aguilera A","year":"2012","unstructured":"A Aguilera, T Garc\u00eda-Muse, R loops: From transcription byproducts to threats to genome stability. Mol Cell 46, 115\u2013124 (2012).","journal-title":"Mol Cell"},{"key":"e_1_3_4_40_2","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1101\/gad.1438306","article-title":"Cotranscriptional processes and their influence on genome stability","volume":"20","author":"Li X","year":"2006","unstructured":"X Li, JL Manley, Cotranscriptional processes and their influence on genome stability. Genes Dev 20, 1838\u20131847 (2006).","journal-title":"Genes Dev"},{"key":"e_1_3_4_41_2","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1101\/gad.1200804","article-title":"Intracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA","volume":"18","author":"Duquette ML","year":"2004","unstructured":"ML Duquette, P Handa, JA Vincent, AF Taylor, N Maizels, Intracellular transcription of G-rich DNAs induces formation of G-loops, novel structures containing G4 DNA. Genes Dev 18, 1618\u20131629 (2004).","journal-title":"Genes Dev"},{"key":"e_1_3_4_42_2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.cell.2005.06.015","article-title":"Escaping the nuclear confines: Signal-dependent pre-mRNA splicing in anucleate platelets","volume":"122","author":"Denis MM","year":"2005","unstructured":"MM Denis, , Escaping the nuclear confines: Signal-dependent pre-mRNA splicing in anucleate platelets. Cell 122, 379\u2013391 (2005).","journal-title":"Cell"},{"key":"e_1_3_4_43_2","doi-asserted-by":"crossref","first-page":"e1002386","DOI":"10.1371\/journal.pgen.1002386","article-title":"Genome instability and transcription elongation impairment in human cells depleted of THO\/TREX","volume":"7","author":"Dom\u00ednguez-S\u00e1nchez MS","year":"2011","unstructured":"MS Dom\u00ednguez-S\u00e1nchez, S Barroso, B G\u00f3mez-Gonz\u00e1lez, R Luna, A Aguilera, Genome instability and transcription elongation impairment in human cells depleted of THO\/TREX. PLoS Genet 7, e1002386 (2011).","journal-title":"PLoS Genet"},{"key":"e_1_3_4_44_2","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.molcel.2012.01.017","article-title":"R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters","volume":"45","author":"Ginno PA","year":"2012","unstructured":"PA Ginno, PL Lott, HC Christensen, I Korf, F Ch\u00e9din, R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Mol Cell 45, 814\u2013825 (2012).","journal-title":"Mol Cell"},{"key":"e_1_3_4_45_2","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.molcel.2011.04.026","article-title":"Human senataxin resolves RNA\/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination","volume":"42","author":"Skourti-Stathaki K","year":"2011","unstructured":"K Skourti-Stathaki, NJ Proudfoot, N Gromak, Human senataxin resolves RNA\/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell 42, 794\u2013805 (2011).","journal-title":"Mol Cell"},{"key":"e_1_3_4_46_2","doi-asserted-by":"crossref","first-page":"2525","DOI":"10.1093\/nar\/22.13.2525","article-title":"Sequence and position requirements for uridylate-rich downstream elements of polyadenylation signals","volume":"22","author":"Chou ZF","year":"1994","unstructured":"ZF Chou, F Chen, J Wilusz, Sequence and position requirements for uridylate-rich downstream elements of polyadenylation signals. Nucleic Acids Res 22, 2525\u20132531 (1994).","journal-title":"Nucleic Acids Res"},{"key":"e_1_3_4_47_2","doi-asserted-by":"crossref","first-page":"8885","DOI":"10.1073\/pnas.85.23.8885","article-title":"Additional low-abundance human small nuclear ribonucleoproteins: U11, U12, etc","volume":"85","author":"Montzka KA","year":"1988","unstructured":"KA Montzka, JA Steitz, Additional low-abundance human small nuclear ribonucleoproteins: U11, U12, etc. Proc Natl Acad Sci USA 85, 8885\u20138889 (1988).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_48_2","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.cell.2012.09.012","article-title":"An SMN-dependent U12 splicing event essential for motor circuit function","volume":"151","author":"Lotti F","year":"2012","unstructured":"F Lotti, , An SMN-dependent U12 splicing event essential for motor circuit function. Cell 151, 440\u2013454 (2012).","journal-title":"Cell"},{"key":"e_1_3_4_49_2","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.cell.2011.11.057","article-title":"Mutation of a U2 snRNA gene causes global disruption of alternative splicing and neurodegeneration","volume":"148","author":"Jia Y","year":"2012","unstructured":"Y Jia, JC Mu, SL Ackerman, Mutation of a U2 snRNA gene causes global disruption of alternative splicing and neurodegeneration. Cell 148, 296\u2013308 (2012).","journal-title":"Cell"},{"key":"e_1_3_4_50_2","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.neuron.2014.06.034","article-title":"DNA damage and its links to neurodegeneration","volume":"83","author":"Madabhushi R","year":"2014","unstructured":"R Madabhushi, L Pan, LH Tsai, DNA damage and its links to neurodegeneration. Neuron 83, 266\u2013282 (2014).","journal-title":"Neuron"},{"key":"e_1_3_4_51_2","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nrm3546","article-title":"The ATM protein kinase: Regulating the cellular response to genotoxic stress, and more","volume":"14","author":"Shiloh Y","year":"2013","unstructured":"Y Shiloh, Y Ziv, The ATM protein kinase: Regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14, 197\u2013210 (2013).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"e_1_3_4_52_2","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/ng1001-184","article-title":"Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene","volume":"29","author":"Date H","year":"2001","unstructured":"H Date, , Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nat Genet 29, 184\u2013188 (2001).","journal-title":"Nat Genet"},{"key":"e_1_3_4_53_2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/ng1001-189","article-title":"The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT\/Zn-finger protein aprataxin","volume":"29","author":"Moreira MC","year":"2001","unstructured":"MC Moreira, , The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT\/Zn-finger protein aprataxin. Nat Genet 29, 189\u2013193 (2001).","journal-title":"Nat Genet"},{"key":"e_1_3_4_54_2","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.nbd.2014.06.014","article-title":"Mitochondrial DNA damage: Molecular marker of vulnerable nigral neurons in Parkinson\u2019s disease","volume":"70","author":"Sanders LH","year":"2014","unstructured":"LH Sanders, , Mitochondrial DNA damage: Molecular marker of vulnerable nigral neurons in Parkinson\u2019s disease. Neurobiol Dis 70, 214\u2013223 (2014).","journal-title":"Neurobiol Dis"},{"key":"e_1_3_4_55_2","doi-asserted-by":"crossref","first-page":"7497","DOI":"10.1093\/nar\/gkm821","article-title":"Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer\u2019s disease","volume":"35","author":"Lovell MA","year":"2007","unstructured":"MA Lovell, WR Markesbery, Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer\u2019s disease. Nucleic Acids Res 35, 7497\u20137504 (2007).","journal-title":"Nucleic Acids Res"},{"key":"e_1_3_4_56_2","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1016\/j.molcel.2011.10.017","article-title":"RNase H and multiple RNA biogenesis factors cooperate to prevent RNA:DNA hybrids from generating genome instability","volume":"44","author":"Wahba L","year":"2011","unstructured":"L Wahba, JD Amon, D Koshland, M Vuica-Ross, RNase H and multiple RNA biogenesis factors cooperate to prevent RNA:DNA hybrids from generating genome instability. Mol Cell 44, 978\u2013988 (2011).","journal-title":"Mol Cell"},{"key":"e_1_3_4_57_2","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/nature13124","article-title":"C9orf72 nucleotide repeat structures initiate molecular cascades of disease","volume":"507","author":"Haeusler AR","year":"2014","unstructured":"AR Haeusler, , C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507, 195\u2013200 (2014).","journal-title":"Nature"},{"key":"e_1_3_4_58_2","doi-asserted-by":"crossref","first-page":"5351","DOI":"10.1093\/nar\/gkm589","article-title":"A persistent RNA.DNA hybrid formed by transcription of the Friedreich ataxia triplet repeat in live bacteria, and by T7 RNAP in vitro","volume":"35","author":"Grabczyk E","year":"2007","unstructured":"E Grabczyk, M Mancuso, MC Sammarco, A persistent RNA.DNA hybrid formed by transcription of the Friedreich ataxia triplet repeat in live bacteria, and by T7 RNAP in vitro. Nucleic Acids Res 35, 5351\u20135359 (2007).","journal-title":"Nucleic Acids Res"},{"key":"e_1_3_4_59_2","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1086\/421054","article-title":"DNA\/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)","volume":"74","author":"Chen YZ","year":"2004","unstructured":"YZ Chen, , DNA\/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 74, 1128\u20131135 (2004).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_4_60_2","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/ng703","article-title":"Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1","volume":"29","author":"Grohmann K","year":"2001","unstructured":"K Grohmann, , Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet 29, 75\u201377 (2001).","journal-title":"Nat Genet"},{"key":"e_1_3_4_61_2","doi-asserted-by":"crossref","first-page":"17463","DOI":"10.1016\/S0021-9258(19)85357-7","article-title":"The human S mu bp-2, a DNA-binding protein specific to the single-stranded guanine-rich sequence related to the immunoglobulin mu chain switch region","volume":"268","author":"Fukita Y","year":"1993","unstructured":"Y Fukita, , The human S mu bp-2, a DNA-binding protein specific to the single-stranded guanine-rich sequence related to the immunoglobulin mu chain switch region. J Biol Chem 268, 17463\u201317470 (1993).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_62_2","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.neuron.2013.07.033","article-title":"Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis","volume":"79","author":"Ling SC","year":"2013","unstructured":"SC Ling, M Polymenidou, DW Cleveland, Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron 79, 416\u2013438 (2013).","journal-title":"Neuron"},{"key":"e_1_3_4_63_2","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.cell.2009.03.006","article-title":"Rethinking ALS: The FUS about TDP-43","volume":"136","author":"Lagier-Tourenne C","year":"2009","unstructured":"C Lagier-Tourenne, DW Cleveland, Rethinking ALS: The FUS about TDP-43. Cell 136, 1001\u20131004 (2009).","journal-title":"Cell"},{"key":"e_1_3_4_64_2","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/nature12270","article-title":"MBNL proteins repress ES-cell-specific alternative splicing and reprogramming","volume":"498","author":"Han H","year":"2013","unstructured":"H Han, , MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature 498, 241\u2013245 (2013).","journal-title":"Nature"},{"key":"e_1_3_4_65_2","doi-asserted-by":"crossref","first-page":"6171","DOI":"10.1038\/ncomms7171","article-title":"ALS-causative mutations in FUS\/TLS confer gain and loss of function by altered association with SMN and U1-snRNP","volume":"6","author":"Sun S","year":"2015","unstructured":"S Sun, , ALS-causative mutations in FUS\/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat Commun 6, 6171 (2015).","journal-title":"Nat Commun"},{"key":"e_1_3_4_66_2","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.febslet.2004.07.010","article-title":"Survival motor neuron protein facilitates assembly of stress granules","volume":"572","author":"Hua Y","year":"2004","unstructured":"Y Hua, J Zhou, Survival motor neuron protein facilitates assembly of stress granules. FEBS Lett 572, 69\u201374 (2004).","journal-title":"FEBS Lett"},{"key":"e_1_3_4_67_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1080\/19491034.2015.1004952","article-title":"R-loops highlight the nucleus in ALS","volume":"6","author":"Salvi JS","year":"2015","unstructured":"JS Salvi, K Mekhail, R-loops highlight the nucleus in ALS. Nucleus 6, 23\u201329 (2015).","journal-title":"Nucleus"},{"key":"e_1_3_4_68_2","first-page":"E7701","article-title":"Two familial ALS proteins function in prevention\/repair of transcription-associated DNA damage","volume":"113","author":"Hill SJ","year":"2016","unstructured":"SJ Hill, , Two familial ALS proteins function in prevention\/repair of transcription-associated DNA damage. Proc Natl Acad Sci USA 113, E7701\u2013E7709 (2016).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_69_2","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1261\/rna.057208.116","article-title":"Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: Implications for spinal muscular atrophy","volume":"22","author":"Garcia EL","year":"2016","unstructured":"EL Garcia, Y Wen, K Praveen, AG Matera, Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: Implications for spinal muscular atrophy. RNA 22, 1215\u20131227 (2016).","journal-title":"RNA"},{"key":"e_1_3_4_70_2","doi-asserted-by":"crossref","first-page":"e93329","DOI":"10.1371\/journal.pone.0093329","article-title":"Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of spinal muscular atrophy (SMA)","volume":"9","author":"Fayzullina S","year":"2014","unstructured":"S Fayzullina, LJ Martin, Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of spinal muscular atrophy (SMA). PLoS One 9, e93329 (2014).","journal-title":"PLoS One"},{"key":"e_1_3_4_71_2","doi-asserted-by":"crossref","first-page":"e1004294","DOI":"10.1371\/journal.pgen.1004294","article-title":"Transcription-associated R-loop formation across the human FMR1 CGG-repeat region","volume":"10","author":"Loomis EW","year":"2014","unstructured":"EW Loomis, LA Sanz, F Chedin, PJ Hagerman, Transcription-associated R-loop formation across the human FMR1 CGG-repeat region. PLoS Genet 10, e1004294 (2014).","journal-title":"PLoS Genet"},{"key":"e_1_3_4_72_2","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nbt.3049","article-title":"Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes","volume":"33","author":"Maury Y","year":"2014","unstructured":"Y Maury, , Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes. Nat Biotechnol 33, 89\u201396 (2014).","journal-title":"Nat Biotechnol"},{"key":"e_1_3_4_73_2","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/bioinformatics\/btq033","article-title":"BEDTools: A flexible suite of utilities for comparing genomic features","volume":"26","author":"Quinlan AR","year":"2010","unstructured":"AR Quinlan, IM Hall, BEDTools: A flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841\u2013842 (2010).","journal-title":"Bioinformatics"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1613181114","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T11:53:58Z","timestamp":1654602838000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1613181114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,7]]},"references-count":73,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2017,3,21]]}},"alternative-id":["10.1073\/pnas.1613181114"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1613181114","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.727380515.793549680","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,7]]},"assertion":[{"value":"2017-03-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}