Dysregulation of X-ray repair cross-complementing 4 expression in the eutopic endometrium of women with endometriosis

in Reproduction
View More View Less
  • 1 Cell Physiology and Pathology Laboratory, Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMR-NIRRCH), Mumbai, India
  • | 2 Department of Pathology, Seth G.S. Medical College and King Edward Memorial Hospital, Parel, Mumbai, India
  • | 3 Sanjeevani Diagnostic Centre and General Maternity Home, Alaknanda Apartment, Dattani Park, Kandivali East, Mumbai, India
  • | 4 Jaslok Hospital and Research Centre, Mumbai, India
  • | 5 Advanced Multi Specialty Hospitals and Criticare Multispecialty Hospital and Research Center, Andheri-West, Mumbai, India
  • | 6 Department of Obstetrics and Gynecology, Seth G.S. Medical College and King Edward Memorial Hospital, Parel, Mumbai, India
  • | 7 Department of Clinical Research, ICMR-NIRRCH, Mumbai, India

Correspondence should be addressed to G Sachdeva; Email: sachdevag@nirrh.res.in
Restricted access

Recent data suggest that the DNA damage response (DDR) is altered in the eutopic endometrium (EE) of women with endometriosis and this probably ensues in response to higher DNA damage encountered by the EE in endometriosis. DDR operates in a tissue-specific manner and involves different pathways depending on the type of DNA lesions. Among these pathways, the non-homologous end joining (NHEJ) pathway plays a critical role in the repair of dsDNA breaks. The present study was undertaken to explore whether NHEJ is affected in the EE of women with endometriosis. Toward this, we focused on the X-ray repair cross-complementing 4 (XRCC4) protein, one of the core components of the NHEJ pathway. Endometrial XRCC4 protein levels in the mid-proliferative phase were found significantly (P  < 0.05) downregulated in women with endometriosis, compared to control women. Investigation of a microarray-based largest dataset in the Gene Expression Omnibus database (GSE51981) revealed a similar trend at the transcript level in the EE of women with endometriosis, compared to control women. Further in vitro studies were undertaken to explore the effects of H2O2-induced oxidative stress on DNA damage, as assessed by γ-H2AX and 8-hydroxy-2’-deoxyguanosine (8-OHdG) immunolocalization, and XRCC4 protein levels in endometrial stromal (hTERT immortalized human endometrial stromal cell line (ThESCs)) and epithelial (Ishikawa) cells. A significant decrease in XRCC4 protein levels and significantly higher localization of γ-H2AX and 8-OHdG were evident in ThESCs and Ishikawa cells experiencing oxidative stress. Overall, the study demonstrates that the endometrial XRCC4 expression is dysregulated in women with endometriosis and this could be due to higher oxidative stress in endometriosis.

Supplementary Materials

 

     An official journal of

    Society for Reproduction and Fertility

 

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 1273 1273 153
Full Text Views 37 37 2
PDF Downloads 49 49 4
  • 1997 Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertility and Sterility 67 817821. (https://doi.org/10.1016/s0015-0282(9781391-x)

    • Search Google Scholar
    • Export Citation
  • Arrington ED, Caldwell MC, Kumaravel TS, Lohani A, Joshi A, Evans MK, Chen HT, Nussenzweig A, Holbrook NJ & Gorospe M 2000 Enhanced sensitivity and long-term G2 arrest in hydrogen peroxide-treated Ku80-null cells are unrelated to DNA repair defects. Free Radical Biology and Medicine 29 11661176. (https://doi.org/10.1016/s0891-5849(0000439-1)

    • Search Google Scholar
    • Export Citation
  • Bane K, Desouza J, Shetty D, Choudhary P, Kadam S, Katkam RR, Fernandes G, Sawant R, Dudhedia U & Warty N et al.2021 Endometrial DNA damage response is modulated in endometriosis. Human Reproduction 36 160174. (https://doi.org/10.1093/humrep/deaa255)

    • Search Google Scholar
    • Export Citation
  • Bolton JL & Thatcher GR 2008 Potential mechanisms of estrogen quinone carcinogenesis. Chemical Research in Toxicology 21 93101. (https://doi.org/10.1021/tx700191p)

    • Search Google Scholar
    • Export Citation
  • Carvalho LF, Rossener R, Azeem A, Malvezzi H, Simoes Abrao M & Agarwal A 2013 From conception to birth – how endometriosis affects the development of each stage of reproductive life. Minerva Ginecologica 65 181198.

    • Search Google Scholar
    • Export Citation
  • Chang HHY, Pannunzio NR, Adachi N & Lieber MR 2017 Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nature Reviews: Molecular Cell Biology 18 495506. (https://doi.org/10.1038/nrm.2017.48)

    • Search Google Scholar
    • Export Citation
  • Chatterjee N & Walker GC 2017 Mechanisms of DNA damage, repair, and mutagenesis. Environmental and Molecular Mutagenesis 58 235263. (https://doi.org/10.1002/em.22087)

    • Search Google Scholar
    • Export Citation
  • Choi YS, Park JH, Lee JH, Yoon JK, Yun BH, Park JH, Seo SK, Sung HJ, Kim HS & Cho S et al.2018 Association between impairment of DNA double strand break repair and decreased ovarian reserve in patients with endometriosis. Frontiers in Endocrinology 9 772. (https://doi.org/10.3389/fendo.2018.00772)

    • Search Google Scholar
    • Export Citation
  • Dai Y, Lin X, Xu W, Lin X, Huang Q, Shi L, Pan Y, Zhang Y, Zhu Y & Li C et al.2019 MiR-210-3p protects endometriotic cells from oxidative stress-induced cell cycle arrest by targeting BARD1. Cell Death and Disease 10 144. (https://doi.org/10.1038/s41419-019-1395-6)

    • Search Google Scholar
    • Export Citation
  • Dassen H, Punyadeera C, Kamps R, Delvoux B, Van Langendonckt A, Donnez J, Husen B, Thole H, Dunselman G & Groothuis P 2007 Estrogen metabolizing enzymes in endometrium and endometriosis. Human Reproduction 22 31483158. (https://doi.org/10.1093/humrep/dem310)

    • Search Google Scholar
    • Export Citation
  • Demitri C, Giuri A, Raucci MG, Giugliano D, Madaghiele M, Sannino A & Ambrosio L 2014 Preparation and characterization of cellulose-based foams via microwave curing. Interface Focus 4 20130053. (https://doi.org/10.1098/rsfs.2013.0053)

    • Search Google Scholar
    • Export Citation
  • Eaton SL, Roche SL, Llavero M, Oldknow KJ, Farquharson C, Gillingwater TH & Wishart TM 2013 Total protein analysis as a reliable loading control for quantitative fluorescent Western blotting. PLoS ONE 8 e72457. (https://doi.org/10.1371/journal.pone.0072457)

    • Search Google Scholar
    • Export Citation
  • Fosang AJ & Colbran RJ 2015 Transparency is the key to quality. Journal of Biological Chemistry 290 2969229694. (https://doi.org/10.1074/jbc.E115.000002)

    • Search Google Scholar
    • Export Citation
  • Ghosh D & Raghavan SC 2021 Nonhomologous end joining: new accessory factors fine tune the machinery. Trends in Genetics 37 582599. (https://doi.org/10.1016/j.tig.2021.03.001)

    • Search Google Scholar
    • Export Citation
  • Hapangama DK, Turner MA, Drury JA, Quenby S, Hart A, Maddick M, Martin-Ruiz C & Von Zglinicki T 2009 Sustained replication in endometrium of women with endometriosis occurs without evoking a DNA damage response. Human Reproduction 24 687696. (https://doi.org/10.1093/humrep/den416)

    • Search Google Scholar
    • Export Citation
  • Hsieh YY, Bau DT, Chang CC, Tsai CH, Chen CP & Tsai FJ 2008 XRCC4 codon 247*A and XRCC4 promoter -1394*T related genotypes but not XRCC4 intron 3 gene polymorphism are associated with higher susceptibility for endometriosis. Molecular Reproduction and Development 75 946951. (https://doi.org/10.1002/mrd.20829)

    • Search Google Scholar
    • Export Citation
  • Hung PJ, Johnson B, Chen BR, Byrum AK, Bredemeyer AL, Yewdell WT, Johnson TE, Lee BJ, Deivasigamani S & Hindi I et al.2018 MRI is a DNA damage response adaptor during classical non-homologous end joining. Molecular Cell 71 332 .e8342.e8. (https://doi.org/10.1016/j.molcel.2018.06.018)

    • Search Google Scholar
    • Export Citation
  • Ingram SP, Warmenhoven JW, Henthorn NT, Smith EAK, Chadwick AL, Burnet NG, Mackay RI, Kirkby NF, Kirkby KJ & Merchant MJ 2019 Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway. Scientific Reports 9 6359. (https://doi.org/10.1038/s41598-019-42901-8)

    • Search Google Scholar
    • Export Citation
  • Jackson SP & Bartek J 2009 The DNA-damage response in human biology and disease. Nature 461 10711078. (https://doi.org/10.1038/nature08467)

  • Joseph S & Mahale SD 2019 Endometriosis KnowledgeBase: a gene-based resource on endometriosis. Database 2019 baz062. (https://doi.org/10.1093/database/baz062)

    • Search Google Scholar
    • Export Citation
  • Kao SH, Huang HC, Hsieh RH, Chen SC, Tsai MC & Tzeng CR 2005 Oxidative damage and mitochondrial DNA mutations with endometriosis. Annals of the New York Academy of Sciences 1042 186194. (https://doi.org/10.1196/annals.1338.021)

    • Search Google Scholar
    • Export Citation
  • Karanjawala ZE, Murphy N, Hinton DR, Hsieh CL & Lieber MR 2002 Oxygen metabolism causes chromosome breaks and is associated with the neuronal apoptosis observed in DNA double-strand break repair mutants. Current Biology 12 397402. (https://doi.org/10.1016/s0960-9822(0200684-x)

    • Search Google Scholar
    • Export Citation
  • Kim YH, Kim SH, Lee HW, Chae HD, Kim CH & Kang BM 2010 Increased viability of endometrial cells by in vitro treatment with di-(2-ethylhexyl) phthalate. Fertility and Sterility 94 24132416. (https://doi.org/10.1016/j.fertnstert.2010.04.027)

    • Search Google Scholar
    • Export Citation
  • Liu X & Zweier JL 2001 A real-time electrochemical technique for measurement of cellular hydrogen peroxide generation and consumption: evaluation in human polymorphonuclear leukocytes. Free Radical Biology and Medicine 31 894901. (https://doi.org/10.1016/s0891-5849(0100665-7)

    • Search Google Scholar
    • Export Citation
  • Lu J, Wang XZ, Zhang TQ, Huang XY, Yao JG, Wang C, Wei ZH, Ma Y, Wu XM & Luo CY et al.2017 Prognostic significance of XRCC4 expression in hepatocellular carcinoma. Oncotarget 8 8795587970. (https://doi.org/10.18632/oncotarget.21360)

    • Search Google Scholar
    • Export Citation
  • Mao Z, Bozzella M, Seluanov A & Gorbunova V 2008 DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells. Cell Cycle 7 29022906. (https://doi.org/10.4161/cc.7.18.6679)

    • Search Google Scholar
    • Export Citation
  • Markkanen E 2017 Not breathing is not an option: how to deal with oxidative DNA damage. DNA Repair 59 82105. (https://doi.org/10.1016/j.dnarep.2017.09.007)

    • Search Google Scholar
    • Export Citation
  • Moritz CP 2017 Tubulin or not tubulin: heading toward total protein staining as loading control in western blots. Proteomics 17 1600189. (https://doi.org/10.1002/pmic.201600189)

    • Search Google Scholar
    • Export Citation
  • Murphy AA, Santanam N & Parthasarathy S 1998 Endometriosis: a disease of oxidative stress? Seminars in Reproductive Endocrinology 16 263273. (https://doi.org/10.1055/s-2007-1016286)

    • Search Google Scholar
    • Export Citation
  • Murray JE, van der Burg M, IJspeert H, Carroll P, Wu Q, Ochi T, Leitch A, Miller ES, Kysela B & Jawad A et al.2015 Mutations in the NHEJ component XRCC4 cause primordial dwarfism. American Journal of Human Genetics 96 412424. (https://doi.org/10.1016/j.ajhg.2015.01.013)

    • Search Google Scholar
    • Export Citation
  • Nasiri N, Moini A, Eftekhari-Yazdi P, Karimian L, Salman-Yazdi R & Arabipoor A 2017 Oxidative stress statues in serum and follicular fluid of women with endometriosis. Cell Journal 18 582587. (https://doi.org/10.22074/cellj.2016.4724)

    • Search Google Scholar
    • Export Citation
  • Ngo C, Chereau C, Nicco C, Weill B, Chapron C & Batteux F 2009 Reactive oxygen species controls endometriosis progression. American Journal of Pathology 175 225234. (https://doi.org/10.2353/ajpath.2009.080804)

    • Search Google Scholar
    • Export Citation
  • Noyes RW, Hertig AT & Rock J 1975 Dating the endometrial biopsy. American Journal of Obstetrics and Gynecology 122 262263. (https://doi.org/10.1016/s0002-9378(1633500-1)

    • Search Google Scholar
    • Export Citation
  • Ochi T, Blackford AN, Coates J, Jhujh S, Mehmood S, Tamura N, Travers J, Wu Q, Draviam VM & Robinson CV et al.2015 PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science 347 185188. (https://doi.org/10.1126/science.1261971)

    • Search Google Scholar
    • Export Citation
  • Osborn BH, Haney AF, Misukonis MA & Weinberg JB 2002 Inducible nitric oxide synthase expression by peritoneal macrophages in endometriosis-associated infertility. Fertility and Sterility 77 4651. (https://doi.org/10.1016/s0015-0282(0102940-5)

    • Search Google Scholar
    • Export Citation
  • Polak G, Barczynski B, Kwasniewski W, Bednarek W, Wertel I, Derewianka-Polak M & Kotarski J 2013 Low-density lipoproteins oxidation and endometriosis. Mediators of Inflammation 2013 624540. (https://doi.org/10.1155/2013/624540)

    • Search Google Scholar
    • Export Citation
  • Practice Committee of the American Society for Reproductive Medicine 2012 Endometriosis and infertility: a committee opinion. Fertility and Sterility 98 591598. (https://doi.org/10.1016/j.fertnstert.2012.05.031)

    • Search Google Scholar
    • Export Citation
  • Prieto L, Quesada JF, Cambero O, Pacheco A, Pellicer A, Codoceo R & Garcia-Velasco JA 2012 Analysis of follicular fluid and serum markers of oxidative stress in women with infertility related to endometriosis. Fertility and Sterility 98 126130. (https://doi.org/10.1016/j.fertnstert.2012.03.052)

    • Search Google Scholar
    • Export Citation
  • Purohit A, Fusi L, Brosens J, Woo LW, Potter BV & Reed MJ 2008 Inhibition of steroid sulphatase activity in endometriotic implants by 667 COUMATE: a potential new therapy. Human Reproduction 23 290297. (https://doi.org/10.1093/humrep/dem308)

    • Search Google Scholar
    • Export Citation
  • Richter C, Marquardt S, Li F, Spitschak A, Murr N, Edelhauser BAH, Iliakis G, Putzer BM & Logotheti S 2019 Rewiring E2F1 with classical NHEJ via APLF suppression promotes bladder cancer invasiveness. Journal of Experimental and Clinical Cancer Research 38 292. (https://doi.org/10.1186/s13046-019-1286-9)

    • Search Google Scholar
    • Export Citation
  • Rothkamm K, Kruger I, Thompson LH & Lobrich M 2003 Pathways of DNA double-strand break repair during the mammalian cell cycle. Molecular and Cellular Biology 23 57065715. (https://doi.org/10.1128/MCB.23.16.5706-5715.2003)

    • Search Google Scholar
    • Export Citation
  • Ruis B, Molan A, Takasugi T & Hendrickson EA 2020 Absence of XRCC4 and its paralogs in human cells reveal differences in outcomes for DNA repair and V(D)J recombination. DNA Repair 85 102738. (https://doi.org/10.1016/j.dnarep.2019.102738)

    • Search Google Scholar
    • Export Citation
  • Saliminejad K, Saket M, Kamali K, Memariani T & Khorram Khorshid HR 2015 DNA repair gene XRCC1 and XRCC4 variations and risk of endometriosis: an association study. Gynecologic and Obstetric Investigation 80 8588. (https://doi.org/10.1159/000366444)

    • Search Google Scholar
    • Export Citation
  • Santulli P, Chouzenoux S, Fiorese M, Marcellin L, Lemarechal H, Millischer AE, Batteux F, Borderie D & Chapron C 2015 Protein oxidative stress markers in peritoneal fluids of women with deep infiltrating endometriosis are increased. Human Reproduction 30 4960. (https://doi.org/10.1093/humrep/deu290)

    • Search Google Scholar
    • Export Citation
  • Scutiero G, Iannone P, Bernardi G, Bonaccorsi G, Spadaro S, Volta CA, Greco P & Nappi L 2017 Oxidative stress and endometriosis: a systematic review of the literature. Oxidative Medicine and Cellular Longevity 2017 7265238. (https://doi.org/10.1155/2017/7265238)

    • Search Google Scholar
    • Export Citation
  • Sharma V, Collins LB, Chen TH, Herr N, Takeda S, Sun W, Swenberg JA & Nakamura J 2016 Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations. Oncotarget 7 2537725390. (https://doi.org/10.18632/oncotarget.8298)

    • Search Google Scholar
    • Export Citation
  • Singh AK, Chattopadhyay R, Chakravarty B & Chaudhury K 2013 Markers of oxidative stress in follicular fluid of women with endometriosis and tubal infertility undergoing IVF. Reproductive Toxicology 42 116124. (https://doi.org/10.1016/j.reprotox.2013.08.005)

    • Search Google Scholar
    • Export Citation
  • Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Tamura R, Mori Y, Yamawaki K, Adachi S, Takahashi T & Kase H et al.2018 Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Reports 24 17771789. (https://doi.org/10.1016/j.celrep.2018.07.037)

    • Search Google Scholar
    • Export Citation
  • Tamaresis JS, Irwin JC, Goldfien GA, Rabban JT, Burney RO, Nezhat C, Depaolo LV & Giudice LC 2014 Molecular classification of endometriosis and disease stage using high-dimensional genomic data. Endocrinology 155 49864999. (https://doi.org/10.1210/en.2014-1490)

    • Search Google Scholar
    • Export Citation
  • Trzeciak AR, Mohanty JG, Jacob KD, Barnes J, Ejiogu N, Lohani A, Zonderman AB, Rifkind JM & Evans MK 2012 Oxidative damage to DNA and single strand break repair capacity: relationship to other measures of oxidative stress in a population cohort. Mutation Research 736 93103. (https://doi.org/10.1016/j.mrfmmm.2012.01.002)

    • Search Google Scholar
    • Export Citation
  • Turgut A, Ozler A, Goruk NY, Tunc SY, Evliyaoglu O & Gul T 2013 Copper, ceruloplasmin and oxidative stress in patients with advanced-stage endometriosis. European Review for Medical and Pharmacological Sciences 17 14721478.

    • Search Google Scholar
    • Export Citation
  • Turkyilmaz E, Yildirim M, Cendek BD, Baran P, Alisik M, Dalgaci F & Yavuz AF 2016 Evaluation of oxidative stress markers and intra-extracellular antioxidant activities in patients with endometriosis. European Journal of Obstetrics, Gynecology, and Reproductive Biology 199 164168. (https://doi.org/10.1016/j.ejogrb.2016.02.027)

    • Search Google Scholar
    • Export Citation
  • Verit FF, Erel O & Celik N 2008 Serum paraoxonase-1 activity in women with endometriosis and its relationship with the stage of the disease. Human Reproduction 23 100104. (https://doi.org/10.1093/humrep/dem340)

    • Search Google Scholar
    • Export Citation
  • Vestergaard AL, Knudsen UB, Munk T, Rosbach H & Martensen PM 2011 Transcriptional expression of type-I interferon response genes and stability of housekeeping genes in the human endometrium and endometriosis. Molecular Human Reproduction 17 243254. (https://doi.org/10.1093/molehr/gaq100)

    • Search Google Scholar
    • Export Citation
  • Webster AD, Barnes DE, Arlett CF, Lehmann AR & Lindahl T 1992 Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene. Lancet 339 15081509. (https://doi.org/10.1016/0140-6736(9291266-b)

    • Search Google Scholar
    • Export Citation
  • Zondervan KT, Becker CM & Missmer SA 2020 Endometriosis. New England Journal of Medicine 382 12441256. (https://doi.org/10.1056/NEJMra1810764)