Skip to main content

Advertisement

SpringerLink
Log in

Regulation of DNA repair in hypoxic cancer cells

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Emerging evidence indicates that the tumor microenvironmental stress of hypoxia can induce genetic instability in cancer cells. We and others have found that the expression levels of key genes within the DNA mismatch repair (MMR) and homologous recombination (HR) pathways are coordinately repressed by hypoxia. These decreases are associated with functional impairments in both MMR and HR repair under hypoxic conditions, and thus they represent a possible mechanistic explanation for the observed phenomenon of hypoxia-induced genetic instability. In parallel, studies also indicate that several DNA damage response factors are activated in response to hypoxia and subsequent reoxygenation, including ATM/ATR, Chkl/Chk2 and BRCA1. Taken together, these findings reveal that hypoxia induces a unique cellular stress response involving an initial, acute DNA damage response to hypoxia and reoxygenation, followed by a chronic response to prolonged hypoxia in which selected DNA repair pathways are coordinately suppressed. In this review, we discuss these pathways and the possible mechanisms involved, as well as the consequences for genetic instability and tumor progression within the tumor microenvironment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Li, C. Y., Little, J. B., Hu, K., Zhang, W., Zhang, L., Dewhirst, M. W., et al. (2001). Persistent genetic instability in cancer cells induced by non-DNA-damaging stress exposures. Cancer Research, 61(2), 428–432.

    PubMed  CAS  Google Scholar 

  2. Paquette, B., & Little, J. B. (1994). In vivo enhancement of genomic instability in minisatellite sequences of mouse C3H/10T1/2 cells transformed in vitro by X-rays. Cancer Research, 54(12), 3173–3178.

    PubMed  CAS  Google Scholar 

  3. Reynolds, T. Y., Rockwell, S., & Glazer, P. M. (1996). Genetic instability induced by the tumor microenvironment. Cancer Research, 56(24), 5754–5757.

    PubMed  CAS  Google Scholar 

  4. Yuan, J., Narayanan, L., Rockwell, S., & Glazer, P. M. (2000). Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH. Cancer Research, 60(16), 4372–4376.

    PubMed  CAS  Google Scholar 

  5. Hammond, E. M., Dorie, M. J., & Giaccia, A. J. (2003). ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. Journal of Biological Chemistry, 278(14), 12207–12213.

    Article  PubMed  CAS  Google Scholar 

  6. Coquelle, A., Pipiras, E., Toledo, F., Buttin, G., & Debatisse, M. (1997). Expression of fragile sites triggers intrachromosomal mammalian gene amplification and sets boundaries to early amplicons. Cell, 89(2), 215–225.

    Article  PubMed  CAS  Google Scholar 

  7. Coquelle, A., Rozier, L., Dutrillaux, B., & Debatisse, M. (2002). Induction of multiple double-strand breaks within an hsr by meganucleaseI-SceI expression or fragile site activation leads to formation of double minutes and other chromosomal rearrangements. Oncogene, 21(50), 7671–7679.

    Article  PubMed  CAS  Google Scholar 

  8. Coquelle, A., Toledo, F., Stern, S., Bieth, A., & Debatisse, M. (1998). A new role for hypoxia in tumor progression: Induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs. Molecular Cell, 2(2), 259–265.

    Article  PubMed  CAS  Google Scholar 

  9. Subarsky, P., & Hill, R. P. (2003). The hypoxic tumour microenvironment and metastatic progression. Clinical & Experimental Metastasis, 20(3), 237–250.

    Article  CAS  Google Scholar 

  10. Young, S. D., & Hill, R. P. (1990). Effects of reoxygenation on cells from hypoxic regions of solid tumors: Analysis of transplanted murine tumors for evidence of DNA overreplication. Cancer Research, 50(16), 5031–5038.

    PubMed  CAS  Google Scholar 

  11. Young, S. D., Marshall, R. S., & Hill, R. P. (1988). Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proceedings of the National Academy of Sciences of the United States of America, 85(24), 9533–9537.

    Article  PubMed  CAS  Google Scholar 

  12. Mihaylova, V. T., Bindra, R. S., Yuan, J., Campisi, D., Narayanan, L., Jensen, R., et al. (2003). Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Molecular & Cellular Biology, 23(9), 3265–3273.

    Article  CAS  Google Scholar 

  13. Koshiji, M., To, K. K., Hammer, S., Kumamoto, K., Harris, A. L., Modrich, P., et al. (2005). HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Molecular Cell, 17(6), 793–803.

    Article  PubMed  CAS  Google Scholar 

  14. Bindra, R. S., & Glazer, P. M. (2007). Co-repression of mismatch repair gene expression by hypoxia in cancer cells: Role of the Myc/Max network. Cancer Letters, (in press).

  15. Chen, H., Yan, Y., Davidson, T. L., Shinkai, Y., & Costa, M. (2006). Hypoxic stress induces dimethylated histone H3 lysine 9 through histone methyltransferase G9a in mammalian cells. Cancer Research, 66(18), 9009–9016.

    Article  PubMed  CAS  Google Scholar 

  16. Francia, G., Green, S. K., Bocci, G., Man, S., Emmenegger, U., Ebos, J. M. L., et al. (2005). Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: Implications for multicellular resistance to alkylating agents. Molecular Cancer Theraphy, 4(10), 1484–1494.

    Article  CAS  Google Scholar 

  17. Papp-Szabo, E., Josephy, P. D., & Coomber, B. L. (2005). Microenvironmental influences on mutagenesis in mammary epithelial cells. International Journal of Cancer, 116(5), 679–685.

    Article  CAS  Google Scholar 

  18. Shahrzad, S., Quayle, L., Stone, C., Plumb, C., Shirasawa, S., Rak, J. W., et al. (2005). Ischemia-induced K-ras mutations in human colorectal cancer cells: Role of microenvironmental regulation of MSH2 expression. Cancer Research, 65(18), 8134–8141.

    Article  PubMed  CAS  Google Scholar 

  19. Bindra, R. S., Gibson, S. L., Meng, A., Westermark, U., Jasin, M., Pierce, A. J., et al. (2005). Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Research, 65(24), 11597–11604.

    Article  PubMed  CAS  Google Scholar 

  20. Bindra, R. S., & Glazer, P. M. (2006). Repression of RAD51 gene expression by E2F4/p130 complexes in hypoxia. Oncogene, (in press).

  21. Meng, A. X., Jalali, F., Cuddihy, A., Chan, N., Bindra, R. S., Glazer, P. M., et al. (2005). Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells. Radiotherapy and Oncology, 76(2), 168–176.

    Article  PubMed  CAS  Google Scholar 

  22. Harris, A. L. (2002). Hypoxia—A key regulatory factor in tumour growth. Nature Reviews Cancer, 2(1), 38–47.

    Article  PubMed  CAS  Google Scholar 

  23. Freiberg, R. A., Hammond, E. M., Dorie, M. J., Welford, S. M., & Giaccia, A. M. (2006). DNA damage during reoxygenation elicits a Chk2-dependent checkpoint response. Molecular and Cellular Biology, 26(5), 1598–1609.

    Article  PubMed  CAS  Google Scholar 

  24. Freiberg, R. A., Krieg, A. J., Giaccia, A. J., & Hammond, E. M. (2006). Checking in on hypoxia/reoxygenation. Cell Cycle, 5(12), 1304–1307.

    PubMed  CAS  Google Scholar 

  25. Gibson, S. L., Bindra, R. S., & Glazer, P. M. (2005). Hypoxia-induced phosphorylation of Chk2 in an ataxia telangiectasia mutated-dependent manner. Cancer Research, 65(23), 10734–10741.

    Article  PubMed  CAS  Google Scholar 

  26. Gibson, S. L., Bindra, R. S., & Glazer, P. M. (2006). CHK2-dependent phosphorylation of BRCA1 in hypoxia. Radiation Research, 166(4), 646–651.

    Article  PubMed  CAS  Google Scholar 

  27. Hammond, E. M., Denko, N. C., Dorie, M. J., Abraham, R. T., & Giaccia, A. J. (2002). Hypoxia links ATR and p53 through replication arrest. Molecular & Cellular Biology, 22(6), 1834–1843.

    Article  CAS  Google Scholar 

  28. Hammond, E. M., Dorie, M. J., & Giaccia, A. J. (2004). Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation. Cancer Research, 64(18), 6556–6562.

    Article  PubMed  CAS  Google Scholar 

  29. Hammond, E. M., Green, S. L., & Giaccia, A. J. (2003). Comparison of hypoxia-induced replication arrest with hydroxyurea and aphidicolin-induced arrest. Mutation Research, 532(1–2), 205–213.

    PubMed  CAS  Google Scholar 

  30. Yao, X., Buermeyer, A. B., Narayanan, L., Tran, D., Baker, S. M., Prolla, T. M., et al. (1999). Different mutator phenotypes in Mlh1-versus Pms2-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 96(12), 6850–6855.

    Article  PubMed  CAS  Google Scholar 

  31. Salnikow, K., Blagosklonny, M. V., Ryan, H., Johnson, R., & Costa, M. (2000). Carcinogenic nickel induces genes involved with hypoxic stress. Cancer Research, 60(1), 38–41.

    PubMed  CAS  Google Scholar 

  32. Mueller-Klieser, W., Freyer, J. P., & Sutherland, R. M. (1986). Influence of glucose and oxygen supply conditions on the oxygenation of multicellular spheroids. British Journal of Cancer, 53(3), 345–353.

    PubMed  CAS  Google Scholar 

  33. Corn, P. G., Ricci, M. S., Scata, K. A., Arsham, A. M., Simon, M. C., Dicker, D. T., et al. (2005). Mxi1 is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biological Therapy, 4(11), 1285–1294.

    CAS  Google Scholar 

  34. Kaidi, A., Williams, A. C., & Paraskeva, C. (2007). Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nature Cell Biology, 9(2), 210–217.

    Article  PubMed  CAS  Google Scholar 

  35. Khaitan, D., Chandna, S., Arya, M. B., & Dwarakanath, B. S. (2006). Establishment and characterization of multicellular spheroids from a human glioma cell line; Implications for tumor therapy. Journal of Translation Med, 4, 12.

    Article  Google Scholar 

  36. Krieg, A. J., Hammond, E. M., & Giaccia, A. J. (2006). Functional analysis of p53 binding under differential stresses. Molecular and Cellular Biology, 26(19), 7030–7045.

    Article  PubMed  CAS  Google Scholar 

  37. Adhikary, S., & Eilers, M. (2005). Transcriptional regulation and transformation by Myc proteins. Naturalist Review of Molecular and Cellular Biology, 6(8), 635–645.

    Article  CAS  Google Scholar 

  38. Kim, J. W., Zeller, K. I., Wang, Y., Jegga, A. G., Aronow, B. J., O’Donnell, K. A., et al. (2004). Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Molecular Cellular Biology, 24(13), 5923–5936.

    Article  PubMed  CAS  Google Scholar 

  39. Nilsson, J. A., & Cleveland, J. L. (2004). Mnt: Master regulator of the Max network. Cell Cycle, 3(5), 588–590.

    PubMed  CAS  Google Scholar 

  40. Bindra, R. S., Schaffer, P. J., Meng, A., Woo, J., Maseide, K., Roth, M. E., et al. (2004). Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Molecular and Cellular Biology, 24(19), 8504–8518.

    Article  PubMed  CAS  Google Scholar 

  41. Thompson, L. H., & Schild, D. (2002). Recombinational DNA repair and human disease. Mutation Research, 509(1–2), 49–78.

    PubMed  CAS  Google Scholar 

  42. Classon, M., & Dyson, N. (2001). p107 and p130: Versatile proteins with interesting pockets. Experimental Cell Research, 264(1), 135–147.

    Article  PubMed  CAS  Google Scholar 

  43. Cobrinik, D. (2005). Pocket proteins and cell cycle control. Oncogene, 24(17), 2796–2809.

    Article  PubMed  CAS  Google Scholar 

  44. Zhu, W., Giangrande, P. H., & Nevins, J. R. (2004). E2Fs link the control of G1/S and G2/M transcription. European Molecular Biology Organization Journal, 23(23), 4615–4626.

    CAS  Google Scholar 

  45. Cam, H., Balciunaite, E., Blais, A., Spektor, A., Scarpulla, R. C., Young, R., et al. (2004). A common set of gene regulatory networks links metabolism and growth inhibition. Molecular Cell, 16(3), 399–411.

    Article  PubMed  CAS  Google Scholar 

  46. Cam, H., & Dynlacht, B. D. (2003). Emerging roles for E2F: Beyond the G1/S transition and DNA replication. Cancer Cell, 3(4), 311–316.

    Article  PubMed  CAS  Google Scholar 

  47. Lin, W. C., Lin, F. T., & Nevins, J. R. (2001). Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes & Development, 15(14), 1833–1844.

    CAS  Google Scholar 

  48. Pediconi, N., Ianari, A., Costanzo, A., Belloni, L., Gallo, R., Cimino, L., et al. (2003). Differential regulation of E2F1 apoptotic target genes in response to DNA damage. Nature Cell Biology, 5(6), 552–558.

    Article  PubMed  CAS  Google Scholar 

  49. Stevens, C., & La Thangue, N. B. (2003). A new role for E2F-1 in checkpoint control. Cell Cycle, 2(5), 435–437.

    PubMed  CAS  Google Scholar 

  50. Stevens, C., & La Thangue, N. B. (2004). The emerging role of E2F-1 in the DNA damage response and checkpoint control. DNA Repair (Amst), 3(8–9), 1071–1079.

    Article  CAS  Google Scholar 

  51. Stevens, C., Smith, L., & La Thangue, N. B. (2003). Chk2 activates E2F-1 in response to DNA damage. Nature Cell Biology, 5(5), 401–409.

    Article  PubMed  CAS  Google Scholar 

  52. Koshiji, M., Kageyama, Y., Pete, A., Horikawa, I., Barrett, J. C., Huang, L. E., et al. (2004). HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. European Molecular Biology Organization Journal, 23(9), 1949–1956.

    CAS  Google Scholar 

  53. Helt, A. M., & Galloway, D. A. (2001). Destabilization of the retinoblastoma tumor suppressor by human papillomavirus type 16 E7 is not sufficient to overcome cell cycle arrest in human keratinocytes. Journal of Virology, 75(15), 6737–6747.

    Article  PubMed  CAS  Google Scholar 

  54. Crook, T., & Vousden, K. H. (1994). Interaction of HPV E6 with p53 and associated proteins. Biochemical Society Transactions, 22(1), 52–55.

    PubMed  CAS  Google Scholar 

  55. Dimitrov, S., Brennerova, M., & Forejt, J. (2001). Expression profiles and intergenic structure of head-to-head oriented Brca1 and Nbr1 genes. Gene, 262(1–2), 89–98.

    Article  PubMed  CAS  Google Scholar 

  56. Xu, C. F., Brown, M. A., Nicolai, H., Chambers, J. A., Griffiths, B. L., & Solomon, E. (1997). Isolation and characterisation of the NBR2 gene which lies head to head with the human BRCA1 gene. Human Molecular Genetics, 6(7), 1057–1062.

    Article  PubMed  CAS  Google Scholar 

  57. Weinmann, A. S., Yan, P. S., Oberley, M. J., Huang, T. H., & Farnham, P. J. (2002). Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. Genes & Development, 16(2), 235–244.

    Article  CAS  Google Scholar 

  58. Wells, J., & Farnham, P. J. (2002). Characterizing transcription factor binding sites using formaldehyde crosslinking and immunoprecipitation. Methods, 26(1), 48–56.

    Article  PubMed  CAS  Google Scholar 

  59. Iwanaga, R., Komori, H., & Ohtani, K. (2004). Differential regulation of expression of the mammalian DNA repair genes by growth stimulation. Oncogene, 23(53), 8581–8590.

    Article  PubMed  CAS  Google Scholar 

  60. Kel, A. E., Kel-Margoulis, O. V., Farnham, P. J., Bartley, S. M., Wingender, E., & Zhang, M. Q. (2001). Computer-assisted identification of cell cycle-related genes: New targets for E2F transcription factors. Journal of Molecular Biology, 309(1), 99–120.

    Article  PubMed  CAS  Google Scholar 

  61. Garriga, J., Limon, A., Mayol, X., Rane, S. G., Albrecht, J. H., Reddy, E. P., et al. (1998). Differential regulation of the retinoblastoma family of proteins during cell proliferation and differentiation. Biochemical Journal, 333(Pt 3), 645–654.

    PubMed  CAS  Google Scholar 

  62. Barrientes, S., Cooke, C., & Goodrich, D. W. (2000). Glutamic acid mutagenesis of retinoblastoma protein phosphorylation sites has diverse effects on function. Oncogene, 19(4), 562–570.

    Article  PubMed  CAS  Google Scholar 

  63. Krucher, N. A., Rubin, E., Tedesco, V. C., Roberts, M. H., Sherry, T. C., & De Leon, G. (2006). Dephosphorylation of Rb (Thr-821) in response to cell stress. Experimental Cell Research, 312(15), 2757–2763.

    Article  PubMed  CAS  Google Scholar 

  64. Lonergan, K. M., Iliopoulos, O., Ohh, M., Kamura, T., Conaway, R. C., Conaway, J. W., et al. (1998). Regulation of hypoxia-inducible mRNAs by the von Hippel–Lindau tumor suppressor protein requires binding to complexes containing elongins B/C and Cul2. Molecular and Cellular Biology, 18(2), 732–741.

    PubMed  CAS  Google Scholar 

  65. Hartman, A. R., & Ford, J. M. (2003). BRCA1 and p53: Compensatory roles in DNA repair. Journal of Molecular Medecine, 81(11), 700–707.

    Article  CAS  Google Scholar 

  66. Moynahan, M. E., Chiu, J. W., Koller, B. H., & Jasin, M. (1999). Brca1 controls homology-directed DNA repair. Molecular Cell, 4(4), 511–518.

    Article  PubMed  CAS  Google Scholar 

  67. Scully, R., Chen, J., Plug, A., Xiao, Y., Weaver, D., Feunteun, J., et al. (1997). Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell, 88(2), 265–275.

    Article  PubMed  CAS  Google Scholar 

  68. Zhang, J., Willers, H., Feng, Z., Ghosh, J. C., Kim, S., Weaver, D. T., et al. (2004). Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Molecular and Cellular Biology, 24(2), 708–718.

    Article  PubMed  CAS  Google Scholar 

  69. Valerie, K., & Povirk, L. F. (2003). Regulation and mechanisms of mammalian double-strand break repair. Oncogene, 22(37), 5792–5812.

    Article  PubMed  CAS  Google Scholar 

  70. Pierce, A. J., Johnson, R. D., Thompson, L. H., & Jasin, M. (1999). XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes & Development, 13(20), 2633–2638.

    Article  CAS  Google Scholar 

  71. Um, J. H., Kang, C. D., Bae, J. H., Shin, G. G., Kim, D. W., Kim, D. W., et al. (2004). Association of DNA-dependent protein kinase with hypoxia inducible factor-1 and its implication in resistance to anticancer drugs in hypoxic tumor cells. Experimental and Molecular Medicine, 36(3), 233–242.

    PubMed  CAS  Google Scholar 

  72. Unruh, A., Ressell, A., Mohamed, H. G., Johnson, R. S., Nadrowitz, R., Richter, E., et al. (2003). The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene, 22(21), 3213–3220.

    Article  PubMed  CAS  Google Scholar 

  73. Bekker-Jensen, S., Lukas, C., Kitagawa, R., Melander, F., Kastan, M. B., Bartek, J., et al. (2006). Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks. Journal of Cell Biology, 173(2), 195–206.

    Article  PubMed  CAS  Google Scholar 

  74. Shiloh, Y. (2003). ATM and related protein kinases: Safeguarding genome integrity. Nature Reviews Cancer, 3(3), 155–168.

    Article  PubMed  CAS  Google Scholar 

  75. Abraham, R. T. (2004). PI 3-kinase related kinases: ‘Big’ players in stress-induced signaling pathways. DNA Repair (Amst), 3(8–9), 883–887.

    Article  CAS  Google Scholar 

  76. Abraham, R. T. (2004). The ATM-related kinase, hSMG-1, bridges genome and RNA surveillance pathways. DNA Repair (Amst), 3(8–9), 919–925.

    Article  CAS  Google Scholar 

  77. Stiff, T., Walker, S. A., Cerosaletti, K., Goodarzi, A. A., Petermann, E., Concannon, P., et al. (2006). ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. European Molecular Biology Organization Journal, 25(24), 5775–5782.

    CAS  Google Scholar 

  78. Bakkenist, C. J., & Kastan, M. B. (2003). DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature, 421(6922), 499–506.

    Article  PubMed  CAS  Google Scholar 

  79. Cortez, D., Guntuku, S., Qin, J., & Elledge, S. J. (2001). ATR and ATRIP: partners in checkpoint signaling. Science, 294(5547), 1713–1716.

    Article  PubMed  CAS  Google Scholar 

  80. Cortez, D., Wang, Y., Qin, J., & Elledge, S. J. (1999). Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science, 286(5442), 1162–1166.

    Article  PubMed  CAS  Google Scholar 

  81. Helt, C. E., Cliby, W. A., Keng, P. C., Bambara, R. A., & O’Reilly, M. A. (2005). Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein exhibit selective target specificities in response to different forms of DNA damage. Journal of Biological Chemistry, 280(2), 1186–1192.

    Article  PubMed  CAS  Google Scholar 

  82. Green, S. L., Freiberg, R. A., & Giaccia, A. J. (2001). p21(Cip1) and p27(Kip1) regulate cell cycle reentry after hypoxic stress but are not necessary for hypoxia-induced arrest. Molecular & Cellular Biology, 21(4), 1196–1206.

    Article  CAS  Google Scholar 

  83. Foray, N., Marot, D., Gabriel, A., Randrianarison, V., Carr, A. M., Perricaudet, M., et al. (2003). A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. European Molecular Biology Organization Journal, 22(11), 2860–2871.

    CAS  Google Scholar 

  84. Hammond, E. M., Mandell, D. J., Salim, A., Krieg, A. J., Johnson, T. M., Shirazi, H. A., et al. (2006). Genome-wide analysis of p53 under hypoxic conditions. Molecular and Cellar Biology, 26(9), 3492–3504.

    Article  PubMed  CAS  Google Scholar 

  85. Zhang, X., Succi, J., Feng, Z., Prithivirajsingh, S., Story, M. D., Legerski, R. J. (2004). Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response. Molecular and Cellular Biology, 24(20), 9207–9220.

    Article  PubMed  CAS  Google Scholar 

  86. Li, S., Ting, N. S., Zheng, L., Chen, P. L., Ziv, Y., Shiloh, Y., et al. (2000). Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature, 406(6792), 210–215.

    Article  PubMed  CAS  Google Scholar 

  87. Chehab, N. H., Malikzay, A., Appel, M., & Halazonetics, T. D. (2000). Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Development, 14(3), 278–288.

    PubMed  CAS  Google Scholar 

  88. Matsuoka, S., Rotman, G., Ogawa, A., Shiloh, J., Tamai, K., & Eledge, S. J. (2000). Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proceedings of the National Academy of Sciences of the United States of America, 97(19), 10389–10394.

    Article  PubMed  CAS  Google Scholar 

  89. Au, W. W., & Henderson, B. R. (2005). The BRCA1 RING and BRCT domains cooperate in targeting BRCA1 to ionizing radiation-induced nuclear foci. Journal of Biological Chemistry, 280(8), 6993–7001.

    Article  PubMed  CAS  Google Scholar 

  90. Thomas, J. E., Smith, M., Tonkinson, J. L., Rubinfeld, B., & Polakis, P. (1997). Induction of phosphorylation on BRCA1 during the cell cycle and after DNA damage. Cell Growth Differ, 8(7), 801–809.

    PubMed  CAS  Google Scholar 

  91. Chen, G. C., Guan, L. S., Yu, J. H., Choi Kim, H. R., & Wang, Z. Y. (2001). Rb-associated protein 46 (RbAp46) inhibits transcriptional transactivation mediated by BRCA1. Biochemical and Biophysical Research Communications, 284(2), 507–514.

    Article  PubMed  CAS  Google Scholar 

  92. Mullan, P. B., Quinn, J. E., & Harkin, D. P. (2006). The role of BRCA1 in transcriptional regulation and cell cycle control. Oncogene, 25(43), 5854–5863.

    Article  PubMed  CAS  Google Scholar 

  93. Gatei, M., Scott, S. P., Filippovitch, I., Soronika, N., Lavin, M. F., Weber, B., et al. (2000). Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Research, 60(12), 3299–3304.

    PubMed  CAS  Google Scholar 

  94. Lee, J. S., Collins, K. M., Brown, A. L., Lee, C. H., & Chung, J. H. (2000). hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature, 404(6774), 201–204.

    Article  PubMed  CAS  Google Scholar 

  95. Okada, S., & Ouchi, T. (2003). Cell cycle differences in DNA damage-induced BRCA1 phosphorylation affect its subcellular localization. Journal of Biological Chemistry, 278(3), 2015–2020.

    Article  PubMed  CAS  Google Scholar 

  96. Venkitaraman, A. R. (2002). Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell, 108(2), 171–182.

    Article  PubMed  CAS  Google Scholar 

  97. Kang, H. J., Kim, H. J., Rin, J.-K., Mattson, T. L., Kim, K. W., Cho, C.-H., et al. (2006). BRCA1 plays a role in the hypoxic response by regulating HIF-1alpha stability and by modulating vascular endothelial growth factor expression. Journal of Biological Chemistry, 281(19), 13047–13056.

    Article  PubMed  CAS  Google Scholar 

  98. Flygare, J., Benson, F., & Hellgren, D. (1996). Expression of the human RAD51 gene during the cell cycle in primary human peripheral blood lymphocytes. Biochimica et Biophysica acta, 1312(3), 231–236.

    PubMed  Google Scholar 

  99. Gudas, J. M., Li, T., Nguyen, H., Jensen, D., Rauscher, F. J. 3rd, Cowan, K. H. (1996). Cell cycle regulation of BRCA1 messenger RNA in human breast epithelial cells. Cell Growth Differ, 7(6), 717–723.

    PubMed  CAS  Google Scholar 

  100. Hammond, E. M., Dorie, M. J., & Giaccia, A. J. (2003). ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. Journal of Biological Chemistry, 278(14), 12207–12213.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Therapeutic Radiology, Yale University School of Medicine, P.O. Box 208040, New Haven, CT, 06520-8040, USA

    Ranjit S. Bindra, Meredith E. Crosby & Peter M. Glazer

  2. Department of Experimental Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA

    Ranjit S. Bindra

  3. Department of Genetics, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520, USA

    Peter M. Glazer

Authors
  1. Ranjit S. Bindra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meredith E. Crosby
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter M. Glazer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter M. Glazer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bindra, R.S., Crosby, M.E. & Glazer, P.M. Regulation of DNA repair in hypoxic cancer cells. Cancer Metastasis Rev 26, 249–260 (2007). https://doi.org/10.1007/s10555-007-9061-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-007-9061-3

Keywords

Search

Navigation