BACKGROUND: Nibrin, as part of the NBN/MRE11/RAD50 complex, is mutated in Nijmegen breakage syndrome (NBS), which leads to impaired DNA damage response and lymphoid malignancy. RESULTS: Telomere length (TL) was markedly reduced in homozygous patients (and comparably so in all chromosomes) by ~40% (qPCR) and was slightly reduced in NBS heterozygotes older than 30 years (~25% in qPCR), in accordance with the respective cancer rates. Humanized cancer-free NBS mice had normal TL. Telomere elongation was inducible by telomerase and/or alternative telomere lengthening but was associated with abnormal expression of telomeric genes involved in aging and/or cell growth. Lymphoblastoid cells from NBS patients with long survival times (>12 years) displayed the shortest telomeres and low caspase 7 activity. CONCLUSIONS: NBS is a secondary telomeropathy. The two-edged sword of telomere attrition enhances the cancer-prone situation in NBS but can also lead to a relatively stable cellular phenotype in tumor survivors. Results suggest a modular model for progeroid syndromes with abnormal expression of telomeric genes as a molecular basis. METHODS: We studied TL and function in 38 homozygous individuals, 27 heterozygotes, one homozygous fetus, six NBS lymphoblastoid cell lines, and humanized NBS mice, all with the same founder NBN mutation: c.657_661del5.

Center for Prenatal Medicine Leipzig Germany

Charité Universitätsmedizin Berlin BCRT Berlin Institute of Health Center for Regenerative Therapies Berlin Germany

Department of Clinical Genetics Institute of Biology and Medical Genetics 2nd Medical School Charles University Prague Czech Republic

Department of Endocrinology and Metabolism Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin Humboldt Universität zu Berlin Berlin Institute of Health Germany

Department of Human Genetics Ruhr University Bochum Bochum Germany

Department of Medical Genetics The Children's Memorial Health Institute Warsaw Poland

Institute of Clinical Chemistry and Laboratory Medicine University of Rostock Rostock Germany

Institute of Clinical Chemistry Red Cross General Hospital Pyongyang Democratic People's Republic of Korea

Institute of Laboratory Medicine Clinical Chemistry and Pathobiochemistry Charité Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin Humboldt Universität zu Berlin Berlin Institute of Health Germany

Institute of Medical and Human Genetics Charité Universitätsmedizin Berlin Berlin Germany

Integrated Functional Genomics Interdisciplinary Center for Clinical Research University of Münster Münster Germany

Zobrazit více v PubMed

Weemaes CM, Hustinx TW, Scheres JM, van Munster PJ, Bakkeren JA, Taalman RD. A new chromosomal instability disorder: the nijmegen breakage syndrome. Acta Paediatr Scand. 1981; 70:557–64. 10.1111/j.1651-2227.1981.tb05740.x PubMed DOI

Varon R, Demuth I, Chrzanowska KH. GeneReviews®: Nijmegen Breakage Syndrome. Seattle (WA); 1993. PubMed

Demuth I, Digweed M. The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by nijmegen breakage syndrome. Oncogene. 2007; 26:7792–98. 10.1038/sj.onc.1210876 PubMed DOI

Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M. Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis. 2012; 7:13. 10.1186/1750-1172-7-13 PubMed DOI PMC

Saar K, Chrzanowska KH, Stumm M, Jung M, Nürnberg G, Wienker TF, Seemanová E, Wegner RD, Reis A, Sperling K. The gene for the ataxia-telangiectasia variant, nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21. Am J Hum Genet. 1997; 60:605–10. PubMed PMC

Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanová E, Cooper PR, Nowak NJ, Stumm M, Weemaes CM, Gatti RA, et al.. Nibrin, a novel DNA double-strand break repair protein, is mutated in nijmegen breakage syndrome. Cell. 1998; 93:467–76. 10.1016/s0092-8674(00)81174-5 PubMed DOI

Seemanova E, Varon R, Vejvalka J, Jarolim P, Seeman P, Chrzanowska KH, Digweed M, Resnick I, Kremensky I, Saar K, Hoffmann K, Dutrannoy V, Karbasiyan M, et al.. The slavic NBN founder mutation: a role for reproductive fitness? PLoS One. 2016; 11:e0167984. 10.1371/journal.pone.0167984 PubMed DOI PMC

Seemanová E, Jarolim P, Seeman P, Varon R, Digweed M, Swift M, Sperling K. Cancer risk of heterozygotes with the NBN founder mutation. J Natl Cancer Inst. 2007; 99:1875–80. 10.1093/jnci/djm251 PubMed DOI

Digweed M, Sperling K. Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. DNA Repair (Amst). 2004; 3:1207–17. 10.1016/j.dnarep.2004.03.004 PubMed DOI

Rai R, Hu C, Broton C, Chen Y, Lei M, Chang S. NBS1 phosphorylation status dictates repair choice of dysfunctional telomeres. Mol Cell. 2017; 65:801–17.e4. 10.1016/j.molcel.2017.01.016 PubMed DOI PMC

Oh J, Symington LS. Role of the Mre11 complex in preserving genome integrity. Genes (Basel). 2018; 9:589. 10.3390/genes9120589 PubMed DOI PMC

Feldser D, Strong MA, Greider CW. Ataxia telangiectasia mutated (atm) is not required for telomerase-mediated elongation of short telomeres. Proc Natl Acad Sci USA. 2006; 103:2249–51. 10.1073/pnas.0511143103 PubMed DOI PMC

Stracker TH, Petrini JH. The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol. 2011; 12:90–103. 10.1038/nrm3047 PubMed DOI PMC

Cesare AJ, Reddel RR. Alternative lengthening of telomeres: models, mechanisms and implications. Nat Rev Genet. 2010; 11:319–30. 10.1038/nrg2763 PubMed DOI

Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003; 13:1549–56. 10.1016/s0960-9822(03)00542-6 PubMed DOI

Attwooll CL, Akpinar M, Petrini JH. The mre11 complex and the response to dysfunctional telomeres. Mol Cell Biol. 2009; 29:5540–51. 10.1128/MCB.00479-09 PubMed DOI PMC

Dimitrova N, de Lange T. Cell cycle-dependent role of MRN at dysfunctional telomeres: ATM signaling-dependent induction of nonhomologous end joining (NHEJ) in G1 and resection-mediated inhibition of NHEJ in G2. Mol Cell Biol. 2009; 29:5552–63. 10.1128/MCB.00476-09 PubMed DOI PMC

Verdun RE, Crabbe L, Haggblom C, Karlseder J. Functional human telomeres are recognized as DNA damage in G2 of the cell cycle. Mol Cell. 2005; 20:551–61. 10.1016/j.molcel.2005.09.024 PubMed DOI

Wu J, Zhang X, Zhang L, Wu CY, Rezaeian AH, Chan CH, Li JM, Wang J, Gao Y, Han F, Jeong YS, Yuan X, Khanna KK, et al.. Skp2 E3 ligase integrates ATM activation and homologous recombination repair by ubiquitinating NBS1. Mol Cell. 2012; 46:351–61. 10.1016/j.molcel.2012.02.018 PubMed DOI PMC

Kim JH, Grosbart M, Anand R, Wyman C, Cejka P, Petrini JH. The Mre11-Nbs1 interface is essential for viability and tumor suppression. Cell Rep. 2017; 18:496–507. 10.1016/j.celrep.2016.12.035 PubMed DOI PMC

Holohan B, Wright WE, Shay JW. Cell biology of disease: telomeropathies: an emerging spectrum disorder. J Cell Biol. 2014; 205:289–99. 10.1083/jcb.201401012 PubMed DOI PMC

Opresko PL, Shay JW. Telomere-associated aging disorders. Ageing Res Rev. 2017; 33:52–66. 10.1016/j.arr.2016.05.009 PubMed DOI PMC

Siwicki JK, Degerman S, Chrzanowska KH, Roos G. Telomere maintenance and cell cycle regulation in spontaneously immortalized t-cell lines from nijmegen breakage syndrome patients. Exp Cell Res. 2003; 287:178–89. 10.1016/s0014-4827(03)00140-x PubMed DOI

Berardinelli F, Sgura A, Di Masi A, Leone S, Cirrone GA, Romano F, Tanzarella C, Antoccia A. Radiation-induced telomere length variations in normal and in nijmegen breakage syndrome cells. Int J Radiat Biol. 2014; 90:45–52. 10.3109/09553002.2014.859400 PubMed DOI

Habib R, Neitzel H, Ernst A, Wong JK, Goryluk-Kozakiewicz B, Gerlach A, Demuth I, Sperling K, Chrzanowska K. Evidence for a pre-malignant cell line in a skin biopsy from a patient with nijmegen breakage syndrome. Mol Cytogenet. 2018; 11:17. 10.1186/s13039-018-0364-6 PubMed DOI PMC

Lansdorp PM, Verwoerd NP, van de Rijke FM, Dragowska V, Little MT, Dirks RW, Raap AK, Tanke HJ. Heterogeneity in telomere length of human chromosomes. Hum Mol Genet. 1996; 5:685–91. 10.1093/hmg/5.5.685 PubMed DOI

Youngren K, Jeanclos E, Aviv H, Kimura M, Stock J, Hanna M, Skurnick J, Bardeguez A, Aviv A. Synchrony in telomere length of the human fetus. Hum Genet. 1998; 102:640–43. 10.1007/s004390050755 PubMed DOI

Habib R. Analysis of telomere length in patients with chromosomal instability syndromes, particularly Nijmegen Breakage Syndrome (NBS) and its mouse model by complementary technologies; Doctoral thesis Charité - Universitätsmedizin, 2012.

Difilippantonio S, Celeste A, Fernandez-Capetillo O, Chen HT, Reina San Martin B, Van Laethem F, Yang YP, Petukhova GV, Eckhaus M, Feigenbaum L, Manova K, Kruhlak M, Camerini-Otero RD, et al.. Role of Nbs1 in the activation of the atm kinase revealed in humanized mouse models. Nat Cell Biol. 2005; 7:675–85. 10.1038/ncb1270 PubMed DOI

Sakellariou D, Chiourea M, Raftopoulou C, Gagos S. Alternative lengthening of telomeres: recurrent cytogenetic aberrations and chromosome stability under extreme telomere dysfunction. Neoplasia. 2013; 15:1301–13. 10.1593/neo.131574 PubMed DOI PMC

Robin JD, Ludlow AT, Batten K, Magdinier F, Stadler G, Wagner KR, Shay JW, Wright WE. Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances. Genes Dev. 2014; 28:2464–76. 10.1101/gad.251041.114 PubMed DOI PMC

Zavadzkas JA, Plyler RA, Bouges S, Koval CN, Rivers WT, Beck CU, Chang EI, Stroud RE, Mukherjee R, Spinale FG. Cardiac-restricted overexpression of extracellular matrix metalloproteinase inducer causes myocardial remodeling and dysfunction in aging mice. Am J Physiol Heart Circ Physiol. 2008; 295:H1394–402. 10.1152/ajpheart.00346.2008 PubMed DOI PMC

Schneider JE, Stork LA, Bell JT, ten Hove M, Isbrandt D, Clarke K, Watkins H, Lygate CA, Neubauer S. Cardiac structure and function during ageing in energetically compromised guanidinoacetate n-methyltransferase (GAMT)-knockout mice - a one year longitudinal MRI study. J Cardiovasc Magn Reson. 2008; 10:9. 10.1186/1532-429X-10-9 PubMed DOI PMC

Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest. 2018; 128:1238–46. 10.1172/JCI95148 PubMed DOI PMC

Kim KM, Noh JH, Bodogai M, Martindale JL, Pandey PR, Yang X, Biragyn A, Abdelmohsen K, Gorospe M. SCAMP4 enhances the senescent cell secretome. Genes Dev. 2018; 32:909–14. 10.1101/gad.313270.118 PubMed DOI PMC

Anholt RR. Olfactomedin proteins: central players in development and disease. Front Cell Dev Biol. 2014; 2:6. 10.3389/fcell.2014.00006 PubMed DOI PMC

Zhang X, Zhao G, Zhang Y, Wang J, Wang Y, Cheng L, Sun M, Rui Y. Activation of JNK signaling in osteoblasts is inversely correlated with collagen synthesis in age-related osteoporosis. Biochem Biophys Res Commun. 2018; 504:771–76. 10.1016/j.bbrc.2018.08.094 PubMed DOI

Marinelli S, Eleuteri C, Vacca V, Strimpakos G, Mattei E, Severini C, Pavone F, Luvisetto S. Effects of age-related loss of p/q-type calcium channels in a mice model of peripheral nerve injury. Neurobiol Aging. 2015; 36:352–64. 10.1016/j.neurobiolaging.2014.07.025 PubMed DOI

Cui H, Kong Y, Xu M, Zhang H. Notch3 functions as a tumor suppressor by controlling cellular senescence. Cancer Res. 2013; 73:3451–59. 10.1158/0008-5472.CAN-12-3902 PubMed DOI PMC

Yang J, Liu K, Yang J, Jin B, Chen H, Zhan X, Li Z, Wang L, Shen X, Li M, Yu W, Mao Z. PIM1 induces cellular senescence through phosphorylation of UHRF1 at Ser311. Oncogene. 2017; 36:4828–42. 10.1038/onc.2017.96 PubMed DOI

Hua S, Ji Z, Quan Y, Zhan M, Wang H, Li W, Li Y, He X, Lu L. Identification of hub genes in hepatocellular carcinoma using integrated bioinformatic analysis. Aging (Albany NY). 2020; 12:5439–68. 10.18632/aging.102969 PubMed DOI PMC

Park S, Park HEH, Son HG, Lee SJV. The role of RNA helicases in aging and lifespan regulation. Translational Medicine of Aging. 2017; 1:24–31. 10.1016/j.tma.2017.08.001 DOI

Zhao S, Weng YC, Yuan SS, Lin YT, Hsu HC, Lin SC, Gerbino E, Song MH, Zdzienicka MZ, Gatti RA, Shay JW, Ziv Y, Shiloh Y, Lee EY. Functional link between ataxia-telangiectasia and nijmegen breakage syndrome gene products. Nature. 2000; 405:473–77. 10.1038/35013083 PubMed DOI

Khincha PP, Dagnall CL, Hicks B, Jones K, Aviv A, Kimura M, Katki H, Aubert G, Giri N, Alter BP, Savage SA, Gadalla SM. Correlation of leukocyte telomere length measurement methods in patients with dyskeratosis congenita and in their unaffected relatives. Int J Mol Sci. 2017; 18:1765. 10.3390/ijms18081765 PubMed DOI PMC

Meyer A, Salewsky B, Spira D, Steinhagen-Thiessen E, Norman K, Demuth I. Leukocyte telomere length is related to appendicular lean mass: cross-sectional data from the berlin aging study II (BASE-II). Am J Clin Nutr. 2016; 103:178–83. 10.3945/ajcn.115.116806 PubMed DOI

Kim W, Ludlow AT, Min J, Robin JD, Stadler G, Mender I, Lai TP, Zhang N, Wright WE, Shay JW. Regulation of the human telomerase gene TERT by telomere position effect-over long distances (TPE-OLD): implications for aging and cancer. PLoS Biol. 2016; 14:e2000016. 10.1371/journal.pbio.2000016 PubMed DOI PMC

Compton SA, Choi JH, Cesare AJ, Ozgür S, Griffith JD. Xrcc3 and Nbs1 are required for the production of extrachromosomal telomeric circles in human alternative lengthening of telomere cells. Cancer Res. 2007; 67:1513–19. 10.1158/0008-5472.CAN-06-3672 PubMed DOI

Wu G, Jiang X, Lee WH, Chen PL. Assembly of functional ALT-associated promyelocytic leukemia bodies requires nijmegen breakage syndrome 1. Cancer Res. 2003; 63:2589–95. PubMed

Barthel FP, Wei W, Tang M, Martinez-Ledesma E, Hu X, Amin SB, Akdemir KC, Seth S, Song X, Wang Q, Lichtenberg T, Hu J, Zhang J, et al.. Systematic analysis of telomere length and somatic alterations in 31 cancer types. Nat Genet. 2017; 49:349–57. 10.1038/ng.3781 PubMed DOI PMC

Krenzlin H, Demuth I, Salewsky B, Wessendorf P, Weidele K, Bürkle A, Digweed M. DNA damage in nijmegen breakage syndrome cells leads to PARP hyperactivation and increased oxidative stress. PLoS Genet. 2012; 8:e1002557. 10.1371/journal.pgen.1002557 PubMed DOI PMC

Melchers A, Stöckl L, Radszewski J, Anders M, Krenzlin H, Kalischke C, Scholz R, Jordan A, Nebrich G, Klose J, Sperling K, Digweed M, Demuth I. A systematic proteomic study of irradiated DNA repair deficient Nbn-mice. PLoS One. 2009; 4:e5423. 10.1371/journal.pone.0005423 PubMed DOI PMC

Petersen S, Saretzki G, von Zglinicki T. Preferential accumulation of single-stranded regions in telomeres of human fibroblasts. Exp Cell Res. 1998; 239:152–60. 10.1006/excr.1997.3893 PubMed DOI

Prowse KR, Greider CW. Developmental and tissue-specific regulation of mouse telomerase and telomere length. Proc Natl Acad Sci USA. 1995; 92:4818–22. 10.1073/pnas.92.11.4818 PubMed DOI PMC

Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997; 91:25–34. 10.1016/s0092-8674(01)80006-4 PubMed DOI

Widmann TA, Herrmann M, Taha N, König J, Pfreundschuh M. Short telomeres in aggressive non-hodgkin’s lymphoma as a risk factor in lymphomagenesis. Exp Hematol. 2007; 35:939–46. 10.1016/j.exphem.2007.03.009 PubMed DOI

Chrzanowska KH, Digweed M, Sperling K, Seemanova E, editors. DNA-repair deficiency and cancer: Lessons from lymphoma. Fulda: Wiley-VCH Verlag GmbH & Co. KGaA; 2009.

Wentzensen IM, Mirabello L, Pfeiffer RM, Savage SA. The association of telomere length and cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2011; 20:1238–50. 10.1158/1055-9965.EPI-11-0005 PubMed DOI PMC

Jäger K, Walter M. Therapeutic targeting of telomerase. Genes (Basel). 2016; 7:39. 10.3390/genes7070039 PubMed DOI PMC

Hahn WC. Role of telomeres and telomerase in the pathogenesis of human cancer. J Clin Oncol. 2003; 21:2034–43. 10.1200/JCO.2003.06.018 PubMed DOI

Luo X, Sturgis EM, Yang Z, Sun Y, Wei P, Liu Z, Wei Q, Li G. Lymphocyte telomere length predicts clinical outcomes of HPV-positive oropharyngeal cancer patients after definitive radiotherapy. Carcinogenesis. 2019; 40:735–41. 10.1093/carcin/bgz019 PubMed DOI PMC

Kolquist KA, Ellisen LW, Counter CM, Meyerson M, Tan LK, Weinberg RA, Haber DA, Gerald WL. Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nat Genet. 1998; 19:182–86. 10.1038/554 PubMed DOI

Wolska-Kuśnierz B, Gregorek H, Chrzanowska K, Piątosa B, Pietrucha B, Heropolitańska-Pliszka E, Pac M, Klaudel-Dreszler M, Kostyuchenko L, Pasic S, Marodi L, Belohradsky BH, Čižnár P, et al., and Inborn Errors Working Party of the Society for European Blood and Marrow Transplantation and the European Society for Immune Deficiencies. Nijmegen breakage syndrome: clinical and immunological features, long-term outcome and treatment options - a retrospective analysis. J Clin Immunol. 2015; 35:538–49. 10.1007/s10875-015-0186-9 PubMed DOI

Li Y, Zhou G, Bruno IG, Zhang N, Sho S, Tedone E, Lai TP, Cooke JP, Shay JW. Transient introduction of human telomerase mRNA improves hallmarks of progeria cells. Aging Cell. 2019; 18:e12979. 10.1111/acel.12979 PubMed DOI PMC

Aguado J, Sola-Carvajal A, Cancila V, Revêchon G, Ong PF, Jones-Weinert CW, Wallén Arzt E, Lattanzi G, Dreesen O, Tripodo C, Rossiello F, Eriksson M, d’Adda di Fagagna F. Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of hutchinson-gilford progeria syndrome. Nat Commun. 2019; 10:4990. 10.1038/s41467-019-13018-3 PubMed DOI PMC

Robin JD, Ludlow AT, Batten K, Gaillard MC, Stadler G, Magdinier F, Wright WE, Shay JW. SORBS2 transcription is activated by telomere position effect-over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy. Genome Res. 2015; 25:1781–90. 10.1101/gr.190660.115 PubMed DOI PMC

Martin GM. Genetic syndromes in man with potential relevance to the pathobiology of aging. Birth Defects Orig Artic Ser. 1978; 14:5–39. PubMed

Martin GM. Genetic modulation of senescent phenotypes in homo sapiens. Cell. 2005; 120:523–32. 10.1016/j.cell.2005.01.031 PubMed DOI

Hofer AC, Tran RT, Aziz OZ, Wright W, Novelli G, Shay J, Lewis M. Shared phenotypes among segmental progeroid syndromes suggest underlying pathways of aging. J Gerontol A Biol Sci Med Sci. 2005; 60:10–20. 10.1093/gerona/60.1.10 PubMed DOI

Neitzel H. A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet. 1986; 73:320–26. 10.1007/BF00279094 PubMed DOI

Kannenberg F, Gorzelniak K, Jäger K, Fobker M, Rust S, Repa J, Roth M, Björkhem I, Walter M. Characterization of cholesterol homeostasis in telomerase-immortalized tangier disease fibroblasts reveals marked phenotype variability. J Biol Chem. 2013; 288:36936–47. 10.1074/jbc.M113.500256 PubMed DOI PMC

Neuner B, Lenfers A, Kelsch R, Jäger K, Brüggmann N, van der Harst P, Walter M. Telomere length is not related to established cardiovascular risk factors but does correlate with red and white blood cell counts in a german blood donor population. PLoS One. 2015; 10:e0139308. 10.1371/journal.pone.0139308 PubMed DOI PMC

Perner S, Brüderlein S, Hasel C, Waibel I, Holdenried A, Ciloglu N, Chopurian H, Nielsen KV, Plesch A, Högel J, Möller P. Quantifying telomere lengths of human individual chromosome arms by centromere-calibrated fluorescence in situ hybridization and digital imaging. Am J Pathol. 2003; 163:1751–56. 10.1016/S0002-9440(10)63534-1 PubMed DOI PMC

Walter M, Forsyth NR, Wright WE, Shay JW, Roth MG. The establishment of telomerase-immortalized tangier disease cell lines indicates the existence of an apolipoprotein a-I-inducible but ABCA1-independent cholesterol efflux pathway. J Biol Chem. 2004; 279:20866–73. 10.1074/jbc.M401714200 PubMed DOI

Kim R. Assoziationsstudie zur klinischen Variabilität bei Patienten mit dem Nijmegen Breakage Syndrom; Doctoral thesis Charité - Universitätsmedizin, 2010.