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Genome integrity and cell proliferation and survival are regulated by an intricate network of pathways that includes cell cycle checkpoints, DNA repair and recombination, and programmed cell death. It makes sense that there should be a coordinated regulation of these different processes, but the components of such mechanisms remain unknown. In this report, we demonstrate that p19INK4d expression enhances cell survival under genotoxic conditions. By using p19INK4d-overexpressing clones, we demonstrated that p19INK4d expression correlates with the cellular resistance to UV treatment with increased DNA repair activity against UV-induced lesions. On the contrary, cells transfected with p19INK4d antisense cDNA show reduced ability to repair DNA damage and increased sensitivity to genotoxic insult when compared with their p19INK4d-overexpressing counterparts. Consistent with these findings, our studies also show that p19INK4d-overexpressing cells present not only a minor accumulation of UV-induced chromosomal aberrations but a lower frequency of spontaneous chromosome abnormalities than p19INK4d-antisense cells. Lastly, we suggest that p19INK4d effects are dissociated from its role as CDK4/6 inhibitor. The results presented herein support a crucial role for p19INK4d in regulating genomic stability and overall cell viability under conditions of genotoxic stress. We propose that p19INK4d would belong to a protein network that would integrate DNA repair, apoptotic and checkpoint mechanisms in order to maintain the genomic integrity. © 2007 Elsevier B.V. All rights reserved.


Documento: Artículo
Título:Cell cycle inhibitor, p19INK4d, promotes cell survival and decreases chromosomal aberrations after genotoxic insult due to enhanced DNA repair
Autor:Scassa, M.E.; Marazita, M.C.; Ceruti, J.M.; Carcagno, A.L.; Sirkin, P.F.; González-Cid, M.; Pignataro, O.P.; Cánepa, E.T.
Filiación:Laboratorio de Biología Molecular, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Ciudad Universitaria Pabellon II, 1428 Buenos Aires, Argentina
Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, 1425 Buenos Aires, Argentina
Instituto de Biología y Medicina Experimental, CONICET, 1428 Buenos Aires, Argentina
Palabras clave:Apoptosis; Cell survival; Chromosomal aberrations; DNA repair; Genotoxic; p19INK4d; complementary DNA; cyclin dependent kinase inhibitor 2D; phosphorus 32; RNA; animal cell; article; cell cycle; cell growth; cell viability; chromosome aberration; clonogenic assay; controlled study; DNA damage; DNA recombination; DNA repair; DNA synthesis; flow cytometry; genotoxicity; growth inhibition; isotope labeling; mouse; nonhuman; Northern blotting; polyacrylamide gel electrophoresis; priority journal; protein content; tumor cell culture; ultraviolet irradiation; Western blotting; Animals; Blotting, Northern; Blotting, Western; Cell Survival; Chromosome Aberrations; Colony-Forming Units Assay; Cyclin-Dependent Kinase Inhibitor p19; DNA Damage; DNA Repair; Genomic Instability; Humans; Immunoprecipitation; Mice; Pyrimidine Dimers; Radiation Tolerance; RNA, Messenger; Thymidine; Ultraviolet Rays
Página de inicio:626
Página de fin:638
Título revista:DNA Repair
Título revista abreviado:DNA Repair
CAS:phosphorus 32, 14596-37-3; RNA, 63231-63-0; CDKN2D protein, human; Cdkn2d protein, mouse; Cyclin-Dependent Kinase Inhibitor p19; Pyrimidine Dimers; RNA, Messenger; Thymidine, 50-89-5


  • Hoeijmakers, J.H., Genome maintenance mechanisms for preventing cancer (2001) Nature, 411, pp. 366-374
  • Lukas, J., Lukas, C., Bartek, J., Mammalian cell cycle checkpoints: signalling pathways and their organization in space and time (2004) DNA Repair (Amst), 3, pp. 997-1007
  • Sancar, A., Lindsey-Boltz, L.A., Unsal-Kacmaz, K., Linn, S., Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints (2004) Annu. Rev. Biochem., 73, pp. 39-85
  • Burtelow, M.A., Roos-Mattjus, P.M., Rauen, M., Babendure, J.R., Karnitz, L.M., Reconstitution and molecular analysis of the hRad9-hHus1-hRad1 (9-1-1) DNA damage responsive checkpoint complex (2001) J. Biol. Chem., 276, pp. 25903-25909
  • Griffith, J.D., Lindsey-Boltz, L.A., Sancar, A., Structures of the human Rad17-replication factor C and checkpoint Rad 9-1-1 complexes visualized by glycerol spray/low voltage microscopy (2002) J. Biol. Chem., 277, pp. 15233-15236
  • Difilippantonio, S., Celeste, A., Fernandez-Capetillo, O., Chen, H.T., Reina San Martin, B., Van Laethem, F., Yang, Y.P., Nussenzweig, A., Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models (2005) Nat. Cell Biol., 7, pp. 675-685
  • Petrini, J.H., Stracker, T.H., The cellular response to DNA double-strand breaks: defining the sensors and mediators (2003) Trends. Cell Biol., 13, pp. 458-462
  • Yoo, H.Y., Kumagai, A., Shevchenko, A., Dunphy, W.G., Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase (2004) Cell, 117, pp. 575-588
  • Jazayeri, A., Falck, J., Lukas, C., Bartek, J., Smith, G.C., Lukas, J., Jackson, S.P., ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks (2006) Nat. Cell Biol., 8, pp. 37-45
  • Shiloh, Y., ATM and related protein kinases: safeguarding genome integrity (2003) Nat. Rev. Cancer., 3, pp. 155-168
  • Heffernan, T.P., Simpson, D.A., Frank, A.R., Heinloth, A.N., Paules, R.S., Cordeiro-Stone, M., Kaufmann, W.K., An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage (2002) Mol. Cell Biol., 22, pp. 8552-8561
  • Bartek, J., Lukas, J., Chk1 and Chk2 kinases in checkpoint control and cancer (2003) Cancer Cell, 3, pp. 421-429
  • Donzelli, M., Draetta, G.F., Regulating mammalian checkpoints through Cdc25 inactivation (2003) EMBO Rep., 4, pp. 671-677
  • Zhou, B.B., Elledge, S.J., The DNA damage response: putting checkpoints in perspective (2000) Nature, 408, pp. 433-439
  • Norbury, C.J., Zhivotovsky, B., DNA damage-induced apoptosis (2004) Oncogene, 23, pp. 2797-2808
  • Zhivotovsky, B., Kroemer, G., Apoptosis and genomic instability (2004) Nat. Rev. Mol. Cell Biol., 5, pp. 752-762
  • Rouse, J., Jackson, S.P., Interfaces between the detection, signaling, and repair of DNA damage (2002) Science, 297, pp. 547-551
  • D'Andrea, A.D., Grompe, M., The Fanconi anaemia/BRCA pathway (2003) Nat. Rev. Cancer, 3, pp. 23-34
  • Rooney, S., Alt, F.W., Lombard, D., Whitlow, S., Eckersdorff, M., Fleming, J., Fugmann, S., Sekiguchi, J., Defective DNA repair and increased genomic instability in Artemis-deficient murine cells (2003) J. Exp. Med., 197, pp. 553-565
  • Roth, D.B., Amplifying mechanisms of lymphomagenesis (2002) Mol. Cell, 10, pp. 1-2
  • Sekiguchi, J., Ferguson, D.O., Chen, H.T., Yang, E.M., Earle, J., Frank, K., Whitlow, S., Alt, F.W., Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development (2001) Proc. Natl. Acad. Sci. U.S.A., 98, pp. 3243-3248
  • Allard, S., Masson, J.Y., Cote, J., Chromatin remodeling and the maintenance of genome integrity (2004) Biochim. Biophys. Acta, 1677, pp. 158-164
  • Rubbi, C.P., Milner, J., p53 is a chromatin accessibility factor for nucleotide excision repair of DNA damage (2003) Embo. J., 22, pp. 975-986
  • Alano, C.C., Ying, W., Swanson, R.A., Poly(ADP-ribose) polymerase-1-mediated cell death in astrocytes requires NAD+ depletion and mitochondrial permeability transition (2004) J. Biol. Chem., 279, pp. 18895-18902
  • Hickman, M.J., Samson, L.D., Apoptotic signaling in response to a single type of DNA lesion, O(6)-methylguanine (2004) Mol. Cell, 14, pp. 105-116
  • Ceruti, J.M., Scassa, M.E., Flo, J.M., Varone, C.L., Canepa, E.T., Induction of p19INK4d in response to ultraviolet light improves DNA repair and confers resistance to apoptosis in neuroblastoma cells (2005) Oncogene, 24, pp. 4065-4080
  • Roussel, M.F., The INK4 family of cell cycle inhibitors in cancer (1999) Oncogene, 18, pp. 5311-5317
  • Pei, X.H., Xiong, Y., Biochemical and cellular mechanisms of mammalian CDK inhibitors: a few unresolved issues (2005) Oncogene, 24, pp. 2787-2795
  • Collado, M., Gil, J., Efeyan, A., Guerra, C., Schuhmacher, A.J., Barradas, M., Benguria, A., Serrano, M., Tumour biology: senescence in premalignant tumours (2005) Nature, 436, p. 642
  • Cunningham, J.J., Roussel, M.F., Cyclin-dependent kinase inhibitors in the development of the central nervous system (2001) Cell Growth Differ., 12, pp. 387-396
  • Zindy, F., Cunningham, J.J., Sherr, C.J., Jogal, S., Smeyne, R.J., Roussel, M.F., Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases (1999) Proc. Natl. Acad. Sci. U.S.A., 96, pp. 13462-13467
  • Sharpless, N.E., Ramsey, M.R., Balasubramanian, P., Castrillon, D.H., DePinho, R.A., The differential impact of p16(INK4a) or p19(ARF) deficiency on cell growth and tumorigenesis (2004) Oncogene, 23, pp. 379-385
  • Bai, F., Pei, X.H., Godfrey, V.L., Xiong, Y., Haploinsufficiency of p18(INK4c) sensitizes mice to carcinogen-induced tumorigenesis (2003) Mol. Cell Biol., 23, pp. 1269-1277
  • Ascoli, M., Characterization of several clonal lines of cultured Leydig tumor cells: gonadotropin receptors and steroidogenic responses (1981) Endocrinology, 108, pp. 88-95
  • Scassa, M.E., Guberman, A.S., Ceruti, J.M., Canepa, E.T., Hepatic nuclear factor 3 and nuclear factor 1 regulate 5-aminolevulinate synthase gene expression and are involved in insulin repression (2004) J. Biol. Chem., 279, pp. 28082-28092
  • Chomczynski, P., Sacchi, N., Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction (1987) Anal. Biochem., 162, pp. 156-159
  • Newton Bishop, J.A., Harland, M., Bennett, D.C., Bataille, V., Goldstein, A.M., Tucker, M.A., Ponder, B.A., Bishop, D.T., Mutation testing in melanoma families: INK4A, CDK4 and INK4D (1999) Br. J. Cancer, 80, pp. 295-300
  • Varone, C.L., Giono, L.E., Ochoa, A., Zakin, M.M., Canepa, E.T., Transcriptional regulation of 5-aminolevulinate synthase by phenobarbital and cAMP-dependent protein kinase (1999) Arch. Biochem. Biophys., 372, pp. 261-270
  • Giono, L.E., Varone, C.L., Canepa, E.T., 5-Aminolaevulinate synthase gene promoter contains two cAMP-response element (CRE)-like sites that confer positive and negative responsiveness to CRE-binding protein (CREB) (2001) Biochem. J., 353, pp. 307-316
  • Koberle, B., Roginskaya, V., Wood, R.D., XPA protein as a limiting factor for nucleotide excision repair and UV sensitivity in human cells (2006) DNA Repair (Amst), 5, pp. 641-648
  • Guan, K.L., Jenkins, C.W., Li, Y., O'Keefe, C.L., Noh, S., Wu, X., Zariwala, M., Xiong, Y., Isolation and characterization of p19INK4d, a p16-related inhibitor specific to CDK6 and CDK4 (1996) Mol. Biol. Cell, 7, pp. 57-70
  • Friedberg, E.C., How nucleotide excision repair protects against cancer (2001) Nat. Rev. Cancer, 1, pp. 22-33
  • Chipchase, M.D., Melton, D.W., The formation of UV-induced chromosome aberrations involves ERCC1 and XPF but not other nucleotide excision repair genes (2002) DNA Repair (Amst), 1, pp. 335-340
  • Sotillo, R., Dubus, P., Martin, J., de la Cueva, E., Ortega, S., Malumbres, M., Barbacid, M., Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors (2001) Embo. J., 20, pp. 6637-6647
  • Sherr, C.J., Principles of tumor suppression (2004) Cell, 116, pp. 235-246
  • Hahn, W.C., Weinberg, R.A., Modelling the molecular circuitry of cancer (2002) Nat. Rev. Cancer, 2, pp. 331-341
  • Sherr, C.J., Roberts, J.M., CDK inhibitors: positive and negative regulators of G1-phase progression (1999) Genes. Dev., 13, pp. 1501-1512
  • Lin, W.C., Lin, F.T., Nevins, J.R., Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation (2001) Genes Dev., 15, pp. 1833-1844
  • Stevens, C., La Thangue, N.B., The emerging role of E2F-1 in the DNA damage response and checkpoint control (2004) DNA Repair (Amst), 3, pp. 1071-1079
  • Gong, F., Kwon, Y., Smerdon, M.J., Nucleotide excision repair in chromatin and the right of entry (2005) DNA Repair (Amst), 4, pp. 884-896
  • Mellon, I., Transcription-coupled repair: a complex affair (2005) Mutat. Res., 577, pp. 155-161
  • Svejstrup, J.Q., Transcription repair coupling factor: a very pushy enzyme (2002) Mol. Cell, 9, pp. 1151-1152
  • Sarker, A.H., Tsutakawa, S.E., Kostek, S., Ng, C., Shin, D.S., Peris, M., Campeau, E., Cooper, P.K., Recognition of RNA polymerase II and transcription bubbles by XPG, CSB, and TFIIH: insights for transcription-coupled repair and Cockayne Syndrome (2005) Mol. Cell, 20, pp. 187-198
  • Tavera-Mendoza, L.E., Wang, T.T., White, J.H., p19INK4D and cell death (2006) Cell Cycle, 5, pp. 596-598
  • Tavera-Mendoza, L., Wang, T.T., Lallemant, B., Zhang, R., Nagai, Y., Bourdeau, V., Ramirez-Calderon, M., White, J.H., Convergence of vitamin D and retinoic acid signalling at a common hormone response element (2006) EMBO Rep., 7, pp. 180-185
  • Laurent, E., Mitchell, D.L., Estrov, Z., Lowery, M., Tucker, S.L., Talpaz, M., Kurzrock, R., Impact of p210(Bcr-Abl) on ultraviolet C wavelength-induced DNA damage and repair (2003) Clin. Cancer Res., 9, pp. 3722-3730
  • Bartkova, J., Thullberg, M., Rajpert-De Meyts, E., Skakkebaek, N.E., Bartek, J., Lack of p19INK4d in human testicular germ-cell tumours contrasts with high expression during normal spermatogenesis (2000) Oncogene, 19, pp. 4146-4150
  • Chatterjee, R., Haines, G.A., Perera, D.M., Goldstone, A., Morris, I.D., Testicular and sperm DNA damage after treatment with fludarabine for chronic lymphocytic leukaemia (2000) Hum. Reprod., 15, pp. 762-766
  • Zindy, F., van Deursen, J., Grosveld, G., Sherr, C.J., Roussel, M.F., INK4d-deficient mice are fertile despite testicular atrophy (2000) Mol. Cell Biol., 20, pp. 372-378


---------- APA ----------
Scassa, M.E., Marazita, M.C., Ceruti, J.M., Carcagno, A.L., Sirkin, P.F., González-Cid, M., Pignataro, O.P.,..., Cánepa, E.T. (2007) . Cell cycle inhibitor, p19INK4d, promotes cell survival and decreases chromosomal aberrations after genotoxic insult due to enhanced DNA repair. DNA Repair, 6(5), 626-638.
---------- CHICAGO ----------
Scassa, M.E., Marazita, M.C., Ceruti, J.M., Carcagno, A.L., Sirkin, P.F., González-Cid, M., et al. "Cell cycle inhibitor, p19INK4d, promotes cell survival and decreases chromosomal aberrations after genotoxic insult due to enhanced DNA repair" . DNA Repair 6, no. 5 (2007) : 626-638.
---------- MLA ----------
Scassa, M.E., Marazita, M.C., Ceruti, J.M., Carcagno, A.L., Sirkin, P.F., González-Cid, M., et al. "Cell cycle inhibitor, p19INK4d, promotes cell survival and decreases chromosomal aberrations after genotoxic insult due to enhanced DNA repair" . DNA Repair, vol. 6, no. 5, 2007, pp. 626-638.
---------- VANCOUVER ----------
Scassa, M.E., Marazita, M.C., Ceruti, J.M., Carcagno, A.L., Sirkin, P.F., González-Cid, M., et al. Cell cycle inhibitor, p19INK4d, promotes cell survival and decreases chromosomal aberrations after genotoxic insult due to enhanced DNA repair. DNA Repair. 2007;6(5):626-638.