Stress induced telomere shortening: longer life with less mutations?

BMC Systems Biology

Ala Trusina¹ 

[1] Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, DK 2100, Copenhagen, Denmark

关键词: Mathematical model;    Genotoxic stress;    Cell-to-cell heterogeneity;    Reactive Oxygen Species (ROS);    Telomere shortening;   

Others  :  1141334
DOI  :  10.1186/1752-0509-8-27

 received in 2012-03-25, accepted in 2014-02-17,  发布年份 2014

【 摘 要 】

Background

Mutations accumulate as a result of DNA damage and imperfect DNA repair machinery. In higher eukaryotes the accumulation and spread of mutations is limited in two primary ways: through p53-mediated programmed cell death and cellular senescence mediated by telomeres. Telomeres shorten at every cell division and cell stops dividing once the shortest telomere reaches a critical length. It has been shown that the rate of telomere attrition is accelerated when cells are exposed to DNA damaging agents. However the implications of this mechanism are not fully understood.

Results

With the help of in silico model we investigate the effect of genotoxic stress on telomere attrition and apoptosis in a population of non-identical replicating cells. When comparing the populations of cells with constant vs. stress-induced rate of telomere shortening we find that stress induced telomere shortening (SITS) increases longevity while reducing mutation rate. Interestingly, however, the effect takes place only when genotoxic stresses (e.g. reactive oxygen species due to metabolic activity) are distributed non-equally among cells.

Conclusions

Our results for the first time show how non-equal distribution of metabolic load (and associated genotoxic stresses) combined with stress induced telomere shortening can delay aging and minimize mutations.

【 授权许可】

   
2014 Trusina; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Tanaka T, Kajstura M, Halicka HD, Traganos F, Darzynkiewicz Z: Constitutive histone H2AX phosphorylation and ATM activation are strongly amplified during mitogenic stimulation of lymphocytes. Cell Prolif 2007, 40:1-13. [http://dx.doi.org/10.1111/j.1365-2184.2007.00417.x webcite]
• [2]Mandal PK, Blanpain C, Rossi DJ: DNA damage response in adult stem cells: pathways and consequences. Nat Rev Mol Cell Biol 2011, 12(3):198-202. [http://dx.doi.org/10.1038/nrm3060 webcite]
• [3]Lukas C, Savic V, Bekker-Jensen S, Doil C, Neumann B, Pedersen RS, Grøfte M, Hickson ID, Bartek J, Lukas J, Chan K L: 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress. Nat Cell Biol 2011, 13(3):243-253. [http://dx.doi.org/10.1038/ncb2201 webcite]
• [4]Huen MSY, Chen J: The DNA damage response pathways: at the crossroad of protein modifications. Cell Res 2008, 18:8-16. [http://dx.doi.org/10.1038/cr.2007.109 webcite]
• [5]Steinboeck F, Hubmann M, Bogusch A, Dorninger P, Lengheimer T, Heidenreich E: The relevance of oxidative stress and cytotoxic DNA lesions for spontaneous mutagenesis in non-replicating yeast cells. Mutat Res 2010, 688(1–2):47-52. [http://dx.doi.org/10.1016/j.mrfmmm.2010.03.006 webcite]
• [6]Schlereth K, Beinoraviciute-Kellner R, Zeitlinger MK, Bretz AC, Sauer M, Charles JP, Vogiatzi F, Leich E, Samans B, Eilers M, Kisker C, Rosenwald A, Stiewe T: DNA binding cooperativity of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol Cell 2010, 38(3):356-368. [http://dx.doi.org/10.1016/j.molcel.2010.02.037 webcite]
• [7]Martens UM, Chavez EA, Poon SS, Schmoor C, Lansdorp PM: Accumulation of short telomeres in human fibroblasts prior to replicative senescence. Exp Cell Res 2000, 256:291-299. [http://dx.doi.org/10.1006/excr.2000.4823 webcite]
• [8]Proctor CJ, Kirkwood TBL: Modelling telomere shortening and the role of oxidative stress. Mech Ageing Dev 2002, 123(4):351-363.
• [9]von Zglinicki T, Pilger R, Sitte N: Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med 2000, 28:64-74.
• [10]Feinerman O, Veiga J, Dorfman JR, Germain RN, Altan-Bonnet G: Variability and robustness in T cell activation from regulated heterogeneity in protein levels. Science 2008, 321(5892):1081-1084. [http://dx.doi.org/10.1126/science.1158013 webcite]
• [11]Spencer SL, Gaudet S, Albeck JG, Burke JM, Sorger PK: Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 2009, 459(7245):428-432. [http://dx.doi.org/10.1038/nature08012 webcite]
• [12]Beckman RA, Loeb LA: Efficiency of carcinogenesis with and without a mutator mutation. Proc Nat Acad Sci USA 2006, 103(38):14140-14145. [http://dx.doi.org/10.1073/pnas.0606271103 webcite]
• [13]Wu L, Hickson ID: RecQ helicases and cellular responses to DNA damage. Mutat Res 2002, 509(1–2):35-47.
• [14]Bartek J, Lukas J, Bartkova J: DNA damage response as an anti-cancer barrier: damage threshold and the concept of ’conditional haploinsufficiency’. Cell Cycle 2007, 6(19):2344-2347.
• [15]Bartek J, Lukas J: DNA damage checkpoints: from initiation to recovery or adaptation. Curr Opin Cell Biol 2007, 19(2):238-245. [http://dx.doi.org/10.1016/j.ceb.2007.02.009 webcite]
• [16]Cox JD, Ang KK: Radiation oncology: rationale, technique, results. St. Louis. Missouri: Mosby Inc.; 2003.
• [17]op den Buijs J, van den Bosch PPJ, Musters MWJM, van Riel NAW: Mathematical modeling confirms the length-dependency of telomere shortening. Mech Ageing Dev 2004, 125(6):437-444. [http://dx.doi.org/10.1016/j.mad.2004.03.007 webcite]
• [18]Farzaneh-Far R, Lin J, Epel E, Lapham K, Blackburn E, Whooley MA: Telomere length trajectory and its determinants in persons with coronary artery disease: longitudinal findings from the heart and soul study. PLoS One 2010, 5:e8612. [http://dx.doi.org/10.1371/journal.pone.0008612 webcite]
• [19]Hemann MT, Strong MA, Hao LY, Greider CW: The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 2001, 107:67-77.
• [20]Hayflick L, Moorhead P: The serial cultivation of human diploid cell strains. Exp Cell Res 1961, 25(3):585-621. [http://dx.doi.org/10.1016/0014-4827(61)90192-6 webcite]
• [21]Reddel RR: Alternative lengthening of telomeres, telomerase, and cancer. Cancer Lett 2003, 194(2):155-162.
• [22]Antal T, Blagoev KB, Trugman SA, Redner S: Aging and immortality in a cell proliferation model. J Theor Biol 2007, 248(3):411-417. [http://dx.doi.org/10.1016/j.jtbi.2007.06.009 webcite]
• [23]de Lange T: Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 2005, 19(18):2100-2110. [http://dx.doi.org/10.1101/gad.1346005 webcite]
• [24]Smith JR, Whitney RG: Intraclonal variation in proliferative potential of human diploid fibroblasts: stochastic mechanism for cellular aging. Science 1980, 207(4426):82-84.
• [25]Passos JF, Saretzki G, Ahmed S, Nelson G, Richter T, Peters H, Wappler I, Birket MJ, Harold G, Schaeuble K, Birch-Machin MA, Kirkwood TBL, von Zglinicki T: Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 2007, 5(5):e110. [http://dx.doi.org/10.1371/journal.pbio.0050110 webcite]
• [26]Passos JF, Saretzki G, von Zglinicki T: DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res 2007, 35(22):7505-7513. [http://dx.doi.org/10.1093/nar/gkm893 webcite]
• [27]von Zglinicki T, Bürkle A, Kirkwood TB: Stress, DNA damage and ageing – an integrative approach. Exp Gerontol 2001, 36(7):1049-1062.
• [28]de Vargas LM, Sobolewski J, Siegel R, Moss LG: Individual beta-cells within the intact islet differentially respond to glucose. J Biol Chem 1997, 272(42):26573-26577. [http://www.jbc.org/content/272/42/26573.abstract webcite]
• [29]Pinlaor S, Hiraku Y, Yongvanit P, Tada-Oikawa S, Ma N, Pinlaor P, Sithithaworn P, Sripa B, Murata M, Oikawa S, Kawanishi S: iNOS-dependent DNA damage via NF-kappaB expression in hamsters infected with Opisthorchis viverrini and its suppression by the antihelminthic drug praziquantel. Int J Cancer 2006, 119(5):1067-1072. [http://dx.doi.org/10.1002/ijc.21893 webcite]
• [30]Tay S, Hughey JJ, Lee TK, Lipniacki T, Quake SR, Covert MW: Single-cell NF-kappaB dynamics reveal digital activation and analogue information processing. Nature 2010, 466(7303):267-271. [http://dx.doi.org/10.1038/nature09145 webcite]
• [31]Snijder B, Pelkmans L: Origins of regulated cell-to-cell variability. Nat Rev Mol Cell Biol 2011, 12(2):119-125. [http://dx.doi.org/10.1038/nrm3044 webcite]
• [32]Webley K, Bond JA, Jones CJ, Blaydes JP, Craig A, Hupp T, Wynford-Thomas D: Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol Cell Biol 2000, 20(8):2803-2808.