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Facioscapulohumeral dystrophy myoblasts efficiently repair moderate levels of oxidative DNA damage

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Abstract

Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy linked to a deletion of a subset of D4Z4 macrosatellite repeats accompanied by a chromatin relaxation of the D4Z4 array on chromosome 4q. In vitro, FSHD primary myoblasts show altered expression of oxidative-related genes and are more susceptible to oxidative stress. Double homeobox 4 (DUX4) gene, encoded within each D4Z4 unit, is normally transcriptionally silenced but is found aberrantly expressed in skeletal muscles of FSHD patients. Its expression leads to a deregulation of DUX4 target genes including those implicated in redox balance. Here, we assessed DNA repair efficiency of oxidative DNA damage in FSHD myoblasts and DUX4-transfected myoblasts. We have shown that the DNA repair activity is altered neither in FSHD myoblasts nor in immortalized human myoblasts transiently expressing DUX4. DNA damage caused by moderate doses of an oxidant is efficiently repaired while FSHD myoblasts exposed for 24 h to high levels of oxidative stress accumulated more DNA damage than normal myoblasts, suggesting that FSHD myoblasts remain more vulnerable to oxidative stress at high doses of oxidants.

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References

  • Barro M, Carnac G, Flavier S, Mercier J, Vassetzky Y, Laoudj-Chenivesse D (2010) Myoblasts from affected and non-affected FSHD muscles exhibit morphological differentiation defects. J Cell Mol Med 14:275–289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bosnakovski D, Xu Z, Gang EJ, Galindo CL, Liu M, Simsek T, Garner HR, Agha-Mohammadi S, Tassin A, Coppee F, Belayew A, Perlingeiro RR, Kyba M (2008) An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies. EMBO J 27:2766–2779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brouwer OF, Padberg GW, Ruys CJ, Brand R, de Laat JA, Grote JJ (1991) Hearing loss in facioscapulohumeral muscular dystrophy. Neurology 41:1878–1881

    Article  CAS  PubMed  Google Scholar 

  • Burdon RH, Gill V, Rice-Evans C (1990) Oxidative stress and tumour cell proliferation. Free Radical Res Commun 11:65–76

    Article  CAS  Google Scholar 

  • Chamberlain JS, Metzger J, Reyes M, Townsend D, Faulkner JA (2007) Dystrophin-deficient mdx mice display a reduced life span and are susceptible to spontaneous rhabdomyosarcoma. FASEB J 21:2195–2204

    Article  CAS  PubMed  Google Scholar 

  • Cheli S, Francois S, Bodega B, Ferrari F, Tenedini E, Roncaglia E, Ferrari S, Ginelli E, Meneveri R (2011) Expression profiling of FSHD-1 and FSHD-2 cells during myogenic differentiation evidences common and distinctive gene dysregulation patterns. PLoS ONE 6:e20966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clapp J, Mitchell LM, Bolland DJ, Fantes J, Corcoran AE, Scotting PJ, Armour JA, Hewitt JE (2007) Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy. Am J Hum Genet 81:264–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dalle-Donne I, Rossi R, Colombo R, Giustarini D, Milzani A (2006) Biomarkers of oxidative damage in human disease. Clin Chem 52:601–623

    Article  CAS  PubMed  Google Scholar 

  • Dhalla NS, Temsah RM, Netticadan T (2000) Role of oxidative stress in cardiovascular diseases. J Hypertens 18:655–673

    Article  CAS  PubMed  Google Scholar 

  • Dmitriev P, Lipinski M, Vassetzky YS (2009) Pearls in the junk: dissecting the molecular pathogenesis of facioscapulohumeral muscular dystrophy. Neuromuscul Disord 19:17–20

    Article  PubMed  Google Scholar 

  • Dmitriev P, Stankevicins L, Ansseau E, Petrov A, Barat A, Dessen P, Robert T, Turki A, Lazar V, Labourer E, Belayew A, Carnac G, Laoudj-Chenivesse D, Lipinski M, Vassetzky YS (2013) Defective regulation of microRNA target genes in myoblasts from facioscapulohumeral dystrophy patients. J Biol Chem 288:34989–35002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dmitriev P, Kairov U, Robert T, Barat A, Lazar V, Carnac G, Laoudj-Chenivesse D, Vassetzky YS (2014) Cancer-related genes in the transcription signature of facioscapulohumeral dystrophy myoblasts and myotubes. J Cell Mol Med 18:208–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Durackova Z (2010) Some current insights into oxidative stress. Physiol Res 59:459–469

    CAS  PubMed  Google Scholar 

  • Fanzani A, Monti E, Donato R, Sorci G (2013) Muscular dystrophies share pathogenetic mechanisms with muscle sarcomas. Trends Mol Med 19:546–554

    Article  CAS  PubMed  Google Scholar 

  • Ferguson DO, Alt FW (2001) DNA double strand break repair and chromosomal translocation: lessons from animal models. Oncogene 20:5572–5579

    Article  CAS  PubMed  Google Scholar 

  • Fernandez K, Serinagaoglu Y, Hammond S, Martin LT, Martin PT (2010) Mice lacking dystrophin or alpha sarcoglycan spontaneously develop embryonal rhabdomyosarcoma with cancer-associated p53 mutations and alternatively spliced or mutant Mdm2 transcripts. Am J Pathol 176:416–434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fitzsimons RB, Gurwin EB, Bird AC (1987) Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy. A general association with genetic and therapeutic implications. Brain 110((Pt 3)):631–648

    Article  PubMed  Google Scholar 

  • Gabriels J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM, Padberg GW, Frants RR, Hewitt JE, Collen D, Belayew A (1999) Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene 236:25–32

    Article  CAS  PubMed  Google Scholar 

  • Gadalla SM, Lund M, Pfeiffer RM, Gortz S, Mueller CM, Moxley RT 3rd, Kristinsson SY, Bjorkholm M, Shebl FM, Hilbert JE, Landgren O, Wohlfahrt J, Melbye M, Greene MH (2011) Cancer risk among patients with myotonic muscular dystrophy. JAMA 306:2480–2486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geng LN, Yao Z, Snider L, Fong AP, Cech JN, Young JM, van der Maarel SM, Ruzzo WL, Gentleman RC, Tawil R, Tapscott SJ (2012) DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell 22:38–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graham C, Chilton-MacNeill S, Zielenska M, Somers GR (2012) The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas. Hum Pathol 43:180–189

    Article  CAS  PubMed  Google Scholar 

  • Halliwell B (2007) Oxidative stress and cancer: have we moved forward? Biochem J 401:1–11

    Article  CAS  PubMed  Google Scholar 

  • Helleday T (2003) Pathways for mitotic homologous recombination in mammalian cells. Mutat Res 532:103–115

    Article  CAS  PubMed  Google Scholar 

  • Iarovaia OV, Rubtsov M, Ioudinkova E, Tsfasman T, Razin SV, Vassetzky YS (2014) Dynamics of double strand breaks and chromosomal translocations. Mol Cancer 13:249

    Article  PubMed  PubMed Central  Google Scholar 

  • Italiano A, Sung YS, Zhang L, Singer S, Maki RG, Coindre JM, Antonescu CR (2012) High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes Chromosom Cancer 51:207–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(Suppl 3):S26–S36 (discussion S36–S28)

    Article  CAS  PubMed  Google Scholar 

  • Kawamura-Saito M, Yamazaki Y, Kaneko K, Kawaguchi N, Kanda H, Mukai H, Gotoh T, Motoi T, Fukayama M, Aburatani H, Takizawa T, Nakamura T (2006) Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet 15:2125–2137

    Article  CAS  PubMed  Google Scholar 

  • Kazakov V, Rudenko D, Schulev J, Pozdnyakov A (2009) Unusual association of FSHD and extramedullary thoracic tumour in the same patient: a case report. Acta Myol 28:76–79

    CAS  PubMed  PubMed Central  Google Scholar 

  • Knoch J, Kamenisch Y, Kubisch C, Berneburg M (2012) Rare hereditary diseases with defects in DNA-repair. Eur J Dermatol 22:443–455

    CAS  PubMed  Google Scholar 

  • Kowaljow V, Marcowycz A, Ansseau E, Conde CB, Sauvage S, Matteotti C, Arias C, Corona ED, Nunez NG, Leo O, Wattiez R, Figlewicz D, Laoudj-Chenivesse D, Belayew A, Coppee F, Rosa AL (2007) The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscul Disord 17:611–623

    Article  PubMed  Google Scholar 

  • Laoudj-Chenivesse D, Carnac G, Bisbal C, Hugon G, Bouillot S, Desnuelle C, Vassetzky Y, Fernandez A (2005) Increased levels of adenine nucleotide translocator 1 protein and response to oxidative stress are early events in facioscapulohumeral muscular dystrophy muscle. J Mol Med 83:216–224

    Article  CAS  PubMed  Google Scholar 

  • Larsen M, Rost S, El Hajj N, Ferbert A, Deschauer M, Walter MC, Schoser B, Tacik P, Kress W, Muller CR (2015) Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1. Eur J Hum Genet 23:808–816

    Article  CAS  PubMed  Google Scholar 

  • Lemmers RJ, Van Overveld PG, Sandkuijl LA, Vrieling H, Padberg GW, Frants RR, van der Maarel SM (2004) Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in facioscapulohumeral muscular dystrophy. Am J Hum Genet 75:44–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camano P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM (2010) A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 329:1650–1653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW, Amell AM, van der Vliet PJ, Almomani R, Straasheijm KR, Krom YD, Klooster R, Sun Y, den Dunnen JT, Helmer Q, Donlin-Smith CM, Padberg GW, van Engelen BG, de Greef JC, Aartsma-Rus AM, Frants RR, de Visser M, Desnuelle C, Sacconi S, Filippova GN, Bakker B, Bamshad MJ, Tapscott SJ, Miller DG, van der Maarel SM (2012) Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet 44:1370–1374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lyle R, Wright TJ, Clark LN, Hewitt JE (1995) The FSHD-associated repeat, D4Z4, is a member of a dispersed family of homeobox-containing repeats, subsets of which are clustered on the short arms of the acrocentric chromosomes. Genomics 28:389–397

    Article  CAS  PubMed  Google Scholar 

  • Marechal A, Zou L (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol 5:a012716

    Article  PubMed  PubMed Central  Google Scholar 

  • Nicco C, Laurent A, Chereau C, Weill B, Batteux F (2005) Differential modulation of normal and tumor cell proliferation by reactive oxygen species. Biomed Pharmacother 59:169–174

    Article  CAS  PubMed  Google Scholar 

  • Padberg GW, Brouwer OF, de Keizer RJ, Dijkman G, Wijmenga C, Grote JJ, Frants RR (1995) On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy. Muscle Nerve Suppl 2:S73–S80

    Article  CAS  Google Scholar 

  • Petrov A, Pirozhkova I, Carnac G, Laoudj D, Lipinski M, Vassetzky YS (2006) Chromatin loop domain organization within the 4q35 locus in facioscapulohumeral dystrophy patients versus normal human myoblasts. Proc Natl Acad Sci USA 103:6982–6987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pirozhkova I, Petrov A, Dmitriev P, Laoudj D, Lipinski M, Vassetzky Y (2008) A functional role for 4qA/B in the structural rearrangement of the 4q35 region and in the regulation of FRG1 and ANT1 in facioscapulohumeral dystrophy. PLoS ONE 3:e3389

    Article  PubMed  PubMed Central  Google Scholar 

  • Sayre LM, Smith MA, Perry G (2001) Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr Med Chem 8:721–738

    Article  CAS  PubMed  Google Scholar 

  • Schmidt WM, Uddin MH, Dysek S, Moser-Thier K, Pirker C, Hoger H, Ambros IM, Ambros PF, Berger W, Bittner RE (2011) DNA damage, somatic aneuploidy, and malignant sarcoma susceptibility in muscular dystrophies. PLoS Genet 7:e1002042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharma V, Harafuji N, Belayew A, Chen YW (2013) DUX4 differentially regulates transcriptomes of human rhabdomyosarcoma and mouse C2C12 cells. PLoS ONE 8:e64691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sirvent N, Trassard M, Ebran N, Attias R, Pedeutour F (2009) Fusion of EWSR1 with the DUX4 facioscapulohumeral muscular dystrophy region resulting from t(4;22)(q35;q12) in a case of embryonal rhabdomyosarcoma. Cancer Genet Cytogenet 195:12–18

    Article  CAS  PubMed  Google Scholar 

  • Snider L, Geng LN, Lemmers RJ, Kyba M, Ware CB, Nelson AM, Tawil R, Filippova GN, van der Maarel SM, Tapscott SJ, Miller DG (2010) Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet 6:e1001181

    Article  PubMed  PubMed Central  Google Scholar 

  • Statland JM, McDermott MP, Heatwole C, Martens WB, Pandya S, van der Kooi EL, Kissel JT, Wagner KR, Tawil R (2013) Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy. Neuromuscul Disord 23:306–312

    Article  PubMed  PubMed Central  Google Scholar 

  • Tawil R, Van Der Maarel SM (2006) Facioscapulohumeral muscular dystrophy. Muscle Nerve 34:1–15

    Article  CAS  PubMed  Google Scholar 

  • Tsumagari K, Chang SC, Lacey M, Baribault C, Chittur SV, Sowden J, Tawil R, Crawford GE, Ehrlich M (2011) Gene expression during normal and FSHD myogenesis. BMC Med Genomics 4:67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tupler R, Berardinelli A, Barbierato L, Frants R, Hewitt JE, Lanzi G, Maraschio P, Tiepolo L (1996) Monosomy of distal 4q does not cause facioscapulohumeral muscular dystrophy. J Med Genet 33:366–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turki A, Hayot M, Carnac G, Pillard F, Passerieux E, Bommart S, Raynaud de Mauverger E, Hugon G, Pincemail J, Pietri S, Lambert K, Belayew A, Vassetzky Y, Juntas Morales R, Mercier J, Laoudj-Chenivesse D (2012) Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction. Free Radic Biol Med 53:1068–1079

    Article  CAS  PubMed  Google Scholar 

  • Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84

    Article  CAS  PubMed  Google Scholar 

  • van der Maarel SM, Tawil R, Tapscott SJ (2011) Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med 17:252–258

    Article  PubMed  PubMed Central  Google Scholar 

  • van Overveld PG, Lemmers RJ, Sandkuijl LA, Enthoven L, Winokur ST, Bakels F, Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM (2003) Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet 35:315–317

    Article  PubMed  Google Scholar 

  • Vanderplanck C, Ansseau E, Charron S, Stricwant N, Tassin A, Laoudj-Chenivesse D, Wilton SD, Coppee F, Belayew A (2011) The FSHD atrophic myotube phenotype is caused by DUX4 expression. PLoS ONE 6:e26820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wallace LM, Garwick SE, Mei W, Belayew A, Coppee F, Ladner KJ, Guttridge D, Yang J, Harper SQ (2011) DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo. Ann Neurol 69:540–552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Win AK, Perattur PG, Pulido JS, Pulido CM, Lindor NM (2012) Increased cancer risks in myotonic dystrophy. Mayo Clin Proc 87:130–135

    Article  PubMed  PubMed Central  Google Scholar 

  • Winokur ST, Barrett K, Martin JH, Forrester JR, Simon M, Tawil R, Chung SA, Masny PS, Figlewicz DA (2003) Facioscapulohumeral muscular dystrophy (FSHD) myoblasts demonstrate increased susceptibility to oxidative stress. Neuromuscul Disord 13:322–333

    Article  PubMed  Google Scholar 

  • Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der Maarel SM, Padberg GW (2004) Ventilatory support in facioscapulohumeral muscular dystrophy. Neurology 63:176–178

    Article  CAS  PubMed  Google Scholar 

  • Wuebbles RD, Long SW, Hanel ML, Jones PL (2010) Testing the effects of FSHD candidate gene expression in vertebrate muscle development. Int J Clin Exp Pathol 3:386–400

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yazici O, Aksoy S, Ozdemir N, Sendur MA, Dogan M, Zengin N (2013) A rare coincidence: facioscapulohumeral muscular dystrophy and breast cancer. Exp Oncol 35:311–312

    CAS  PubMed  Google Scholar 

  • Yoshimoto M, Graham C, Chilton-MacNeill S, Lee E, Shago M, Squire J, Zielenska M, Somers GR (2009) Detailed cytogenetic and array analysis of pediatric primitive sarcomas reveals a recurrent CIC-DUX4 fusion gene event. Cancer Genet Cytogenet 195:1–11

    Article  CAS  PubMed  Google Scholar 

  • Zeng W, de Greef JC, Chen YY, Chien R, Kong X, Gregson HC, Winokur ST, Pyle A, Robertson KD, Schmiesing JA, Kimonis VE, Balog J, Frants RR, Ball AR Jr, Lock LF, Donovan PJ, van der Maarel SM, Yokomori K (2009) Specific loss of histone H3 lysine 9 trimethylation and HP1gamma/cohesin binding at D4Z4 repeats is associated with facioscapulohumeral dystrophy (FSHD). PLoS Genet 5:e1000559

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This research was supported by the MEGAFSHD grant from the Association Française contre les Myopathies (AFM) to YSV.

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Authors and Affiliations

  1. UMR 8126, CNRS, Univ. Paris-Sud, Institut de Cancérologie Gustave-Roussy, Université Paris Saclay, 94805, Villejuif, France

    Yara Bou Saada, Carla Dib, Petr Dmitriev, Marc Lipinski & Yegor S. Vassetzky

  2. INSERM U-1046, 371 Avenue du Doyen Gaston Giraud, 34295, Montpellier, France

    Gilles Carnac & Dalila Laoudj-Chenivesse

  3. ER030-EDST, Department of Life and Earth Sciences, Faculty of Sciences II, Lebanese University, Beirut, Lebanon

    Aline Hamade

  4. Koltzov Institute of Developmental Biology, Moscow, 117334, Russia

    Yegor S. Vassetzky

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  1. Yara Bou Saada
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Bou Saada, Y., Dib, C., Dmitriev, P. et al. Facioscapulohumeral dystrophy myoblasts efficiently repair moderate levels of oxidative DNA damage. Histochem Cell Biol 145, 475–483 (2016). https://doi.org/10.1007/s00418-016-1410-2

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