Skip to main content

Advertisement

SpringerLink
Log in

Tumor suppressor Ing1b facilitates DNA repair and prevents oxidative stress induced cell death

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Inhibitor of growth (ING) family of proteins are known to coordinate with histone acetyltransferases and regulate the key events of cell cycle and DNA repair. Previous work from our lab showed that Ing1b regulated the nucleotide excision repair by facilitating histone acetylation and subsequent chromatin relaxation. Further, it was also shown that Ing1b protected the cells from genomic instability induced cell death by promoting ubiquitination of proliferating cell nuclear antigen (PCNA). In the present study we explored the role of Ing1b in the repair of oxidized DNA and prevention of oxidative stress induced genotoxic cell death. Using HCT116 cells we show that Ing1b protein expression is induced by treatment with H2O2. Ing1b lacking cells showed decreased ability to repair the oxidized DNA. PCNA monoubiquitination, a critical event of DNA repair was blunted in Ing1b knock down cells and augmented in Ing1b over expressing cells. Moreover, oxidative stress induced cell death was higher in cells lacking Ing1b whereas it was lower in Ing1b over expressing cells. Finally we show that inhibition of histone deacetylases, rescued the Ing1b knock down cells from cytotoxic effects of H2O2 treatment.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Drews G, Krippeit-Drews P, Dufer M (2010) Oxidative stress and beta-cell dysfunction. Pflugers Arch 460(4):703–718. doi:10.1007/s00424-010-0862-9

    Article  CAS  PubMed  Google Scholar 

  2. Bokov A, Chaudhuri A, Richardson A (2004) The role of oxidative damage and stress in aging. Mech Ageing Dev 125(10–11):811–826. doi:10.1016/j.mad.2004.07.009

    Article  CAS  PubMed  Google Scholar 

  3. Maynard S, Schurman SH, Harboe C, de Souza-Pinto NC, Bohr VA (2009) Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30(1):2–10. doi:10.1093/carcin/bgn250

    Article  CAS  PubMed  Google Scholar 

  4. Gonfloni S, Maiani E, Di Bartolomeo C, Diederich M, Cesareni G (2012) Oxidative Stress, DNA Damage, and c-Abl Signaling: at the Crossroad in Neurodegenerative Diseases? Int J Cell Biol 2012:683097. doi:10.1155/2012/683097

    Article  PubMed Central  PubMed  Google Scholar 

  5. Limberg JK, Harrell JW, Johansson R, Eldridge MW, Proctor LT, Sebranek JJ, Schrage WG (2013) Microvascular function in younger adults with obesity and metabolic syndrome: role of oxidative stress. Am J Physiol Heart Circ Physiol. doi:10.1152/ajpheart.00291.2013

    Google Scholar 

  6. Neeley WL, Essigmann JM (2006) Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products. Chem Res Toxicol 19(4):491–505. doi:10.1021/tx0600043

    Article  CAS  PubMed  Google Scholar 

  7. Scott TL, Rangaswamy S, Wicker CA, Izumi T (2013) Repair of oxidative DNA damage and cancer—recent progress in DNA base excision repair. Antioxid Redox Signal. doi:10.1089/ars.2013.5529

    PubMed  Google Scholar 

  8. Wilson DM 3rd, Bohr VA (2007) The mechanics of base excision repair, and its relationship to aging and disease. DNA Repair (Amst) 6(4):544–559. doi:10.1016/j.dnarep.2006.10.017

    Article  CAS  Google Scholar 

  9. Zlatanou A, Despras E, Braz-Petta T, Boubakour-Azzouz I, Pouvelle C, Stewart GS, Nakajima S, Yasui A, Ishchenko AA, Kannouche PL (2011) The hMsh2–hMsh6 complex acts in concert with monoubiquitinated PCNA and Pol eta in response to oxidative DNA damage in human cells. Mol Cell 43(4):649–662. doi:10.1016/j.molcel.2011.06.023

    Article  CAS  PubMed  Google Scholar 

  10. Willis J, Patel Y, Lentz BL, Yan S (2013) APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress. Proc Natl Acad Sci USA 110(26):10592–10597. doi:10.1073/pnas.1301445110

    Article  CAS  PubMed  Google Scholar 

  11. Aguissa-Toure AH, Wong RP, Li G (2011) The ING family tumor suppressors: from structure to function. Cell Mol Life Sci 68(1):45–54. doi:10.1007/s00018-010-0509-1

    Article  CAS  PubMed  Google Scholar 

  12. Ceruti JM, Ogara MF, Menendez C, Palmero I, Canepa ET (2013) Inhibitor of growth 1 (ING1) acts at early steps of multiple DNA repair pathways. Mol Cell Biochem 378(1–2):117–126. doi:10.1007/s11010-013-1601-2

    Article  CAS  PubMed  Google Scholar 

  13. Jafarnejad SM, Li G (2012) Regulation of p53 by ING family members in suppression of tumor initiation and progression. Cancer Metastasis Rev 31(1–2):55–73. doi:10.1007/s10555-011-9329-5

    Article  CAS  PubMed  Google Scholar 

  14. Kuo WH, Wang Y, Wong RP, Campos EI, Li G (2007) The ING1b tumor suppressor facilitates nucleotide excision repair by promoting chromatin accessibility to XPA. Exp Cell Res 313(8):1628–1638. doi:10.1016/j.yexcr.2007.02.010

    Article  CAS  PubMed  Google Scholar 

  15. Li G, Piche B (2010) ING2 in cell cycle regulation. Cell Cycle 9(19):3846. doi:10.4161/cc.9.19.13382

    Article  CAS  PubMed  Google Scholar 

  16. Li J, Wang Y, Wong RP, Li G (2009) The role of ING tumor suppressors in UV stress response and melanoma progression. Curr Drug Targets 10(5):455–464

    Article  CAS  PubMed  Google Scholar 

  17. Li N, Li Q, Cao X, Zhao G, Xue L, Tong T (2011) The tumor suppressor p33ING1b upregulates p16INK4a expression and induces cellular senescence. FEBS Lett 585(19):3106–3112. doi:10.1016/j.febslet.2011.08.044

    Article  CAS  PubMed  Google Scholar 

  18. Wang J, Chin MY, Li G (2006) The novel tumor suppressor p33ING2 enhances nucleotide excision repair via inducement of histone H4 acetylation and chromatin relaxation. Cancer Res 66(4):1906–1911. doi:10.1158/0008-5472.CAN-05-3444

    Article  CAS  PubMed  Google Scholar 

  19. Wang Y, Wang J, Li G (2006) Leucine zipper-like domain is required for tumor suppressor ING2-mediated nucleotide excision repair and apoptosis. FEBS Lett 580(16):3787–3793. doi:10.1016/j.febslet.2006.05.065

    Article  CAS  PubMed  Google Scholar 

  20. Thakur S, Feng X, Qiao Shi Z, Ganapathy A, Kumar Mishra M, Atadja P, Morris D, Riabowol K (2012) ING1 and 5-azacytidine act synergistically to block breast cancer cell growth. PLoS One 7(8):e43671. doi:10.1371/journal.pone.0043671

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Doyon Y, Cayrou C, Ullah M, Landry AJ, Cote V, Selleck W, Lane WS, Tan S, Yang XJ, Cote J (2006) ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell 21(1):51–64. doi:10.1016/j.molcel.2005.12.007

    Article  CAS  PubMed  Google Scholar 

  22. Vieyra D, Loewith R, Scott M, Bonnefin P, Boisvert FM, Cheema P, Pastyryeva S, Meijer M, Johnston RN, Bazett-Jones DP, McMahon S, Cole MD, Young D, Riabowol K (2002) Human ING1 proteins differentially regulate histone acetylation. J Biol Chem 277(33):29832–29839. doi:10.1074/jbc.M200197200

    Article  CAS  PubMed  Google Scholar 

  23. Wong RP, Lin H, Khosravi S, Piche B, Jafarnejad SM, Chen DW, Li G (2011) Tumour suppressor ING1b maintains genomic stability upon replication stress. Nucleic Acids Res 39(9):3632–3642. doi:10.1093/nar/gkq1337

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Kannouche PL, Wing J, Lehmann AR (2004) Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage. Mol Cell 14(4):491–500

    Article  CAS  PubMed  Google Scholar 

  25. Wang Y, Li G (2006) ING3 promotes UV-induced apoptosis via Fas/caspase-8 pathway in melanoma cells. J Biol Chem 281(17):11887–11893. doi:10.1074/jbc.M511309200

    Article  CAS  PubMed  Google Scholar 

  26. Qiao Y, Spitz MR, Guo Z, Hadeyati M, Grossman L, Kraemer KH, Wei Q (2002) Rapid assessment of repair of ultraviolet DNA damage with a modified host-cell reactivation assay using a luciferase reporter gene and correlation with polymorphisms of DNA repair genes in normal human lymphocytes. Mutat Res 509(1–2):165–174

    Article  CAS  PubMed  Google Scholar 

  27. Wang S, Gong Z, Chen R, Liu Y, Li A, Li G, Zhou J (2009) JWA regulates XRCC1 and functions as a novel base excision repair protein in oxidative-stress-induced DNA single-strand breaks. Nucleic Acids Res 37(6):1936–1950. doi:10.1093/nar/gkp054

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Garate M, Campos EI, Bush JA, Xiao H, Li G (2007) Phosphorylation of the tumor suppressor p33(ING1b) at Ser-126 influences its protein stability and proliferation of melanoma cells. FASEB J 21(13):3705–3716. doi:10.1096/fj.07-8069com

    Article  CAS  PubMed  Google Scholar 

  29. Garate M, Wong RP, Campos EI, Wang Y, Li G (2008) NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of the tumour suppressor p33(ING1b). EMBO Rep 9(6):576–581. doi:10.1038/embor.2008.48

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Kielbassa C, Roza L, Epe B (1997) Wavelength dependence of oxidative DNA damage induced by UV and visible light. Carcinogenesis 18(4):811–816

    Article  CAS  PubMed  Google Scholar 

  31. Roth SY, Denu JM, Allis CD (2001) Histone acetyltransferases. Annu Rev Biochem 70:81–120. doi:10.1146/annurev.biochem.70.1.81

    Article  CAS  PubMed  Google Scholar 

  32. Reed SH (2011) Nucleotide excision repair in chromatin: damage removal at the drop of a HAT. DNA Repair (Amst) 10(7):734–742. doi:10.1016/j.dnarep.2011.04.029

    Article  CAS  Google Scholar 

  33. Yu S, Teng Y, Waters R, Reed SH (2011) How chromatin is remodelled during DNA repair of UV-induced DNA damage in Saccharomyces cerevisiae. PLoS Genet 7(6):e1002124. doi:10.1371/journal.pgen.1002124

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Sengupta N, Seto E (2004) Regulation of histone deacetylase activities. J Cell Biochem 93(1):57–67. doi:10.1002/jcb.20179

    Article  CAS  PubMed  Google Scholar 

  35. Gambino V, De Michele G, Venezia O, Migliaccio P, Dall’Olio V, Bernard L, Minardi SP, Della Fazia MA, Bartoli D, Servillo G, Alcalay M, Luzi L, Giorgio M, Scrable H, Pelicci PG, Migliaccio E (2013) Oxidative stress activates a specific p53 transcriptional response that regulates cellular senescence and aging. Aging Cell 12(3):435–445. doi:10.1111/acel.12060

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Bauer M, Goldstein M, Christmann M, Becker H, Heylmann D, Kaina B (2011) Human monocytes are severely impaired in base and DNA double-strand break repair that renders them vulnerable to oxidative stress. Proc Natl Acad Sci USA 108(52):21105–21110. doi:10.1073/pnas.1111919109

    Article  CAS  PubMed  Google Scholar 

  37. Bauer M, Goldstein M, Heylmann D, Kaina B (2012) Human monocytes undergo excessive apoptosis following temozolomide activating the ATM/ATR pathway while dendritic cells and macrophages are resistant. PLoS One 7(6):e39956. doi:10.1371/journal.pone.0039956

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Bhandaru M, Yang W, Rotte A, Pasham V, Lang F (2012) Regulation of Na+/H+ exchanger in dendritic cells by Akt2. Pflugers Arch 463(2):355–363. doi:10.1007/s00424-011-1015-5

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr Ronald P C Wong for the valuable discussions during the course of the project. This project was supported by grants from Canadian Institute of Health Research (MOP-93810).

Conflict of interest

The authors declared that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Dermatology and Skin Science, University of British Columbia, Research Pavilion, 828 West, 10th Avenue, Vancouver, BC, V5Z 1L8, Canada

    Anand Rotte, Gang Li & Madhuri Bhandaru

Authors
  1. Anand Rotte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Madhuri Bhandaru
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anand Rotte.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rotte, A., Li, G. & Bhandaru, M. Tumor suppressor Ing1b facilitates DNA repair and prevents oxidative stress induced cell death. Apoptosis 19, 518–526 (2014). https://doi.org/10.1007/s10495-013-0940-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-013-0940-5

Keywords

Search

Navigation