Abstract
Molecular alterations leading to genome instability play a key role in tumor development. The basic causes of genetic instability of tumor cells are considered, including distorted regulation of the intracellular level of endogenous mutagens, in particular, reactive oxygen species; impaired fidelity of DNA replication and mitotic chromosome segregation; defects in DNA repair systems; and inactivation of cell-cycle checkpoints, which arrest proliferation of abnormal cells. The review discusses the causes of the tissue specificity of carcinogenesis due to genetic instability, as well as prospects of developing new means to control tumor growth via diminishing genome instability or using defects in the control of genome integrity for selective elimination of neoplastic cells.
Similar content being viewed by others
References
Hanahan D., Weinberg R.A. 2000. The hallmarks of cancer. Cell. 100, 57–70.
Vogelstein B., Kinzler K. 2004. Cancer genes and the pathways they control. Nat. Med. 10, 789–799.
Kopnin B.P. 2004. Molecular mechanisms of carcinogenesis, In: Entsiklopediya klinicheskoi onkologii (Encyclopedia of Clinical Oncology), Ed. Davidov M.I., Moscow: RLS Press, pp. 34–53.
Sieber O.M., Heinimann K., Tomlinson I.P. 2003. Genomic instability: The engine of tumorigenesis? Nat. Rev. Cancer. 3, 701–708.
Sablina A.A., Budanov A.V., Ilyinskaya G.V., Agapova L.S., Kravchenko J.E., Chumakov P.M. 2005. The antioxidant function of the p53 tumor suppressor. Nat. Med. 11, 1306–1313.
Kopnin P.B., Agapova L.S., Kopnin B.P., Chumakov P.M. 2006. Novel Ras-sestrins pathways contribute to oncogenic Ras-induced ROS up-regulation and genetic instability. Cancer Res. Submitted.
Vafa O., Wade M., Kern S., Beeche M., Pandita T.K., Hampton G.M., Wahl G.M. 2002. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: A mechanism for oncogene-induced genetic instability. Mol. Cell. 9, 1031–1044.
Carcamo J.M., Golde D.W. 2006. Antioxidants prevent oxidative DNA damage and cellular transformation elicited by the over-expression of c-MYC. Mutat. Res. 593, 64–79.
Hussain S.P., Amstad P., He P., Robles A., Lupold S., Kaneko I., Ichimiya M., Sengupta S., Mechanic L., Okamura S., Hofseth L.J., Moake M., Nagashima M., Forrester K.S., Harris C.C. 2004. p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis. Cancer Res. 64, 2350–2356.
Yoon K.A., Nakamura Y., Arakawa H. 2004. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J. Hum. Genet. 49, 134–140.
Budanov A.V., Sablina A.A., Feinstein E., Koonin E.V., Chumakov P.M. 2004. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science. 304, 596–600.
Seru R., Mondola P., Damiano S., Svegliati S., Agnese S., Avvedimento E.V., Santillo M. 2004. HaRas activates the NADPH oxidase complex in human neuroblastoma cells via extracellular signal-regulated kinase 1/2 pathway. J. Neurochem. 91, 613–622.
Dang C.V., Li F., Lee L.A. 2005. Could MYC induction of mitochondrial biogenesis be linked to ROS production and genomic instability? Cell Cycle. 4, 1465–1466.
Lala P.K., Chakraborty C. 2001. Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol. 2, 149–156.
Takahashi M., Mutoh M., Shoji Y., Kamanaka Y., Naka M., Maruyama T., Sugimura T., Wakabayashi K. 2003. Transfection of K-rasAsp12 cDNA markedly elevates IL-1β-and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells. Oncogene. 22, 7667–7676.
Calvisi D.F., Ladu S., Hironaka K., Factor V.M., Thorgeirsson S.S. 2004. Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-α transgenic mouse model of liver cancer. J. Hepatol. 41, 815–822.
Philip M., Rowley D.A., Schreiber H. 2004. Inflammation as a tumor promoter in cancer induction. Semin. Cancer Biol. 14, 433–439.
Sawa T., Ohshima H. 2006. Nitrative DNA damage in inflammation and its possible role in carcinogenesis. Nitric Oxide. 14, 91–100.
Cougot D., Neuveut C., Buendia M.A. 2005. HBV induced carcinogenesis. J. Clin. Virol. 34,Suppl. 1, S75–S78.
Machida K., Cheng K.T., Lai C.K., Jeng K.S., Sung V.M., Lai M.M. 2006. Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation. J. Virol. 80, 7199–7207.
Kunkel T. 2003. Considering the cancer consequences of altered DNA polymerase function. Cancer Cell. 3, 105–110.
Bavoux C., Hoffmann J.S., Cazaux C. 2005. Adaptation to DNA damage and stimulation of genetic instability: The double-edged sword mammalian DNA polymerase κ. Biochimie. 87, 637–646.
Canitrot Y., Lautier D., Laurent G., Frechet M., Ahmed A., Turhan A.G., Salles B., Cazaux C., Hoffmann J.S. 1999. Mutator phenotype of BCR-ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase β. Oncogene. 18, 2676–2680.
Machida K., Cheng K.T., Sung V.M., Shimodaira S., Lindsay K.L., Levine A.M., Lai M.Y., Lai M.M. 2004. Hepatitis C virus induces a mutator phenotype: Enhanced mutations of immunoglobulin and protooncogenes. Proc. Natl. Acad. Sci. USA. 101, 4262–4267.
Epeldegui M., Hung Y.P., McQuay A., Ambinder R.F., Martinez-Maza O. 2007. Infection of human B cells with Epstein-Barr virus results in the expression of somatic hypermutation-inducing molecules and in the accrual of oncogene mutations. Mol. Immunol. 44, 934–942.
Bergoglio V., Pillaire M.J., Lacroix-Triki M., Raynaud-Messina B., Canitrot Y., Bieth A., Gares M., Wright M., Delsol G., Loeb L.A., Cazaux C., Hoffmann J.S. 2002. Deregulated DNA polymerase β induces chromosome instability and tumorigenesis. Cancer Res. 62, 3511–3514.
Bavoux C., Leopoldino A.M., Bergoglio V., O-Wang J., Ogi T., Bieth A., Judde J.G., Pena S.D., Poupon M.F., Helleday T., Tagawa M., Machado C., Hoffmann J.S., Cazaux C. 2005. Up-regulation of the error-prone DNA polymerase κ promotes pleiotropic genetic alterations and tumorigenesis. Cancer Res. 65, 325–330.
Goldsby R.E., Lawrence N.A., Hays L.E., Olmsted E.A., Chen X., Singh M., Preston B.D. 2001. Defective DNA polymerase-δ proofreading causes cancer susceptibility in mice. Nat. Med. 7, 638–639.
Fukasawa K. 2005. Centrosome amplification, chromosome instability and cancer development. Cancer Lett. 230, 6–19.
McDermott K.M., Zhang J., Holst C.R., Kozakiewicz K., Singla V., Tlsty T.D. 2006. p16INK4a prevents centrosome dysfunction and genomic instability in primary cells. PLoS Biol. 4, 350–365.
Chae S., Yun C., Um H., Lee J.H., Cho H. 2005. Centrosome amplification and multinuclear phenotypes are induced by hydrogen peroxide. Exp. Mol. Med. 37, 482–487.
Deng C.X. 2006. BRCA1: Cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res. 34, 1416–1426.
Sankaran S., Starita L.M., Simons A.M., Parvin J.D. 2006. Identification of domains of BRCA1 critical for the ubiquitin-dependent inhibition of centrosome function. Cancer Res. 66, 4100–4107.
Rouse J., Jackson S.P. 2002. Interfaces between the detection, signaling, and repair of DNA damage. Science. 297, 547–551.
Kastan M.B., Bartek J. 2004. Cell-cycle checkpoints and cancer. Nature. 432, 316–323.
Sancar A., Lindsey-Boltz L.A., Unsal-Kacmaz K., Linn S. 2004. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85.
Fluckiger A.C., Marcy G., Marchand M., Negre D., Cosset F.L., Mitalipov S., Wolf D., Savatier P., Dehay C. 2006. Cell cycle features of primate embryonic stem cells. Stem Cells. 24, 547–556.
Jiricny J. 2006. The multifaceted mismatch-repair system. Nat. Rev. Mol. Cell. Biol. 7, 335–346.
Chao E.C., Lipkin S.M. 2006. Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis. Nucleic Acids Res. 34, 840–852.
Dip R., Camenisch U., Naegeli H. 2004. Mechanisms of DNA damage recognition and strand discrimination in human nucleotide excision repair. DNA Repair (Amsterdam). 3, 1409–1423.
Cleaver J.E. 2005. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat. Rev. Cancer. 5, 564–573.
O’Driscoll M., Jeggo P.A. 2006. The role of double-strand break repair: Insights from human genetics. Nat. Rev. Genet. 7, 45–54.
Lavin M.F., Birrell G., Chen P., Kozlov S., Scott S., Gueven N. 2005. ATM signaling and genomic stability in response to DNA damage. Mutat Res. 569, 123–132.
Lavin M.F., Gueven N. 2006. The complexity of p53 stabilization and activation. Cell Death Differ. 13, 941–950.
Levine A.J., Hu W., Feng Z. 2006. The p53 pathway: What questions remain to be explored? Cell Death Differ. 13, 1027–1036.
Rohaly G., Chemnitz J., Dehde S., Nunez A.M., Heukeshoven J., Deppert W., Dornreiter I. 2005. A novel human p53 isoform is an essential element of the ATR-intra-S phase checkpoint. Cell. 122, 21–32.
Fukushima T., Zapata J.M., Singha N.C., Thomas M., Kress C.L., Krajewska M., Krajewski S., Ronai Z., Reed J.C., Matsuzawa S. 2006. Critical function for SIP, a ubiquitin E3 ligase component of the β-catenin degradation pathway, for thymocyte development and G1 checkpoint. Immunity. 24, 29–39.
Yoon K., Smart R.C. 2004. C/EBPalpha is a DNA damage-inducible p53-regulated mediator of the G1 check-point in keratinocytes. Mol. Cell Biol. 24, 10650–10660.
Doumont G., Martoriati A., Beekman C., Bogaerts S., Mee P.J., Bureau F., Colombo E., Alcalay M., Bellefroid E., Marchesi F., Scanziani E., Pelicci P.G., Marine J.C. 2005. G1 checkpoint failure and increased tumor susceptibility in mice lacking the novel p53 target Ptprv. EMBO J. 24, 3093–3103.
Scoumanne A., Chen X. 2006. The epithelial cell transforming sequence 2, a guanine nucleotide exchange factor for Rho GTPases, is repressed by p53 via protein methyltransferases and is required for G1-S transition. Cancer Res. 66, 6271–6279.
Braithwaite A.W., Del Sal G., Lu X. 2006. Some p53-binding proteins that can function as arbiters of life and death. Cell Death Differ. 13, 984–993.
Wu X., Webster S.R., Chen J. 2001. Characterization of tumor-associated Chk2 mutations. J. Biol. Chem. 276, 2971–2974.
Kops G.J., Weaver B.A., Cleveland D.W. 2005. On the road to cancer: Aneuploidy and the mitotic checkpoint. Nat. Rev. Cancer. 5, 773–785.
Yu X., Minter-Dykhouse K., Malureanu L., Zhao W.M., Zhang D., Merkle C.J., Ward I.M., Saya H., Fang G., van Deursen J., Chen J. 2005. Chfr is required for tumor suppression and Aurora A regulation. Nat. Genet. 37, 401–406.
Sengupta S., Harris C.C. 2005. p53: Traffic cop at the crossroads of DNA repair and recombination. Nat. Rev. Mol. Cell. Biol. 6, 44–55.
Agapova L., Ivanov A., Sablina A., Kopnin P., Sokova O., Chumakov P., Kopnin B. 1999. p53-dependent effects of RAS oncogene on chromosome stability and cell cycle checkpoints. Oncogene. 18, 3135–3142.
Agapova L.S., Volodina J.L., Chumakov P.M., Kopnin B.P. 2004. Activation of Ras-Ral pathway attenuates p53-independent DNA damage G2 checkpoint. J. Biol. Chem. 279, 36,382–36,389.
Cox A.D., Der C.J. 2003. The dark side of Ras: Regulation of apoptosis. Oncogene. 22, 8999–9006.
Pruitt K., Ulku A.S., Frantz K., Rojas R.J., Muniz-Medina V.M., Rangnekar V.M., Der C.J., Shields J.M. 2005. Ras-mediated loss of the pro-apoptotic response protein Par-4 is mediated by DNA hypermethylation through Raf-independent and Raf-dependent signaling cascades in epithelial cells. J. Biol. Chem. 280, 23,363–23,370.
Le Gac G., Esteve P.O., Ferec C., Pradhan S. 2006. DNA damage-induced downregulation of human Cdc25c and Cdc2 is mediated by co-operation between p53 and maintenance DNA (cytosine-5) methyltransferase 1. J. Biol. Chem. 281, 24,161–24,170.
Rosen E.M., Fan S., Isaacs C. 2005. BRCA1 in hormonal carcinogenesis: Basic and clinical research. Endocr. Relat. Cancer. 12, 533–548.
Shin S., Verma I.M. 2003. BRCA2 cooperates with histone acetyltransferases in androgen receptor-mediated transcription. Proc. Natl. Acad. Sci. USA. 100, 7201–7206.
Chao E.C., Lipkin S.M. 2006. Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis. Nucleic Acids Res. 34, 840–852.
Schlissel M.S., Kaffer C.R., Curry J.D. 2006. Leukemia and lymphoma: A cost of doing business for adaptive immunity. Genes Dev. 20, 1539–1544.
Kopnin P.B., Kravchenko I.V., Furalyov V.A., Pylev L.N., Kopnin B.P. 2004. Cell type-specific effects of asbestos on intracellular ROS levels, DNA oxidation and G1 cell cycle checkpoint. Oncogene. 23, 8834–8840.
Farmer H., McCabe N., Lord C.J., Tutt A.N., Johnson D.A., Richardson T.B., Santarosa M., Dillon K.J., Hickson I., Knights C., Martin N.M., Jackson S.P., Smith G.C., Ashworth A. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 434, 917–921.
Author information
Authors and Affiliations
Additional information
Original Russian Text © B.P. Kopnin, 2007, published in Molekulyarnaya Biologiya, 2007, Vol. 41, No. 2, pp. 369–380.
Rights and permissions
About this article
Cite this article
Kopnin, B.P. Genome instability and oncogenesis. Mol Biol 41, 329–339 (2007). https://doi.org/10.1134/S0026893307020136
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1134/S0026893307020136