OSA's Digital Library

Biomedical Optics Express

Biomedical Optics Express

  • Editor: Joseph A. Izatt
  • Vol. 4, Iss. 4 — Apr. 1, 2013
  • pp: 559–568

Intense THz pulses cause H2AX phosphorylation and activate DNA damage response in human skin tissue

Lyubov V. Titova, Ayesheshim K. Ayesheshim, Andrey Golubov, Dawson Fogen, Rocio Rodriguez-Juarez, Frank A. Hegmann, and Olga Kovalchuk  »View Author Affiliations

Biomedical Optics Express, Vol. 4, Issue 4, pp. 559-568 (2013)

View Full Text Article

Enhanced HTML    Acrobat PDF (1434 KB)

Browse Journals / Lookup Meetings

Browse by Journal and Year


Lookup Conference Papers

Close Browse Journals / Lookup Meetings

Article Tools



Recent emergence and growing use of terahertz (THz) radiation for medical imaging and public security screening raise questions on reasonable levels of exposure and health consequences of this form of electromagnetic radiation. In particular, picosecond-duration THz pulses have shown promise for novel diagnostic imaging techniques. However, the effects of THz pulses on human cells and tissues thus far remain largely unknown. We report on the investigation of the biological effects of pulsed THz radiation on artificial human skin tissues. We observe that exposure to intense THz pulses for ten minutes leads to a significant induction of H2AX phosphorylation, indicating that THz pulse irradiation may cause DNA damage in exposed skin tissue. At the same time, we find a THz-pulse-induced increase in the levels of several proteins responsible for cell-cycle regulation and tumor suppression, suggesting that DNA damage repair mechanisms are quickly activated. Furthermore, we find that the cellular response to pulsed THz radiation is significantly different from that induced by exposure to UVA (400 nm).

© 2013 OSA

OCIS Codes
(170.0170) Medical optics and biotechnology : Medical optics and biotechnology
(170.1420) Medical optics and biotechnology : Biology
(170.6930) Medical optics and biotechnology : Tissue
(170.7160) Medical optics and biotechnology : Ultrafast technology

ToC Category:
Optical Therapies and Photomodificaton

Original Manuscript: December 19, 2012
Revised Manuscript: February 1, 2013
Manuscript Accepted: February 14, 2013
Published: March 14, 2013

Lyubov V. Titova, Ayesheshim K. Ayesheshim, Andrey Golubov, Dawson Fogen, Rocio Rodriguez-Juarez, Frank A. Hegmann, and Olga Kovalchuk, "Intense THz pulses cause H2AX phosphorylation and activate DNA damage response in human skin tissue," Biomed. Opt. Express 4, 559-568 (2013)

Sort:  Author  |  Year  |  Journal  |  Reset  


  1. D. M. Mittleman, Sensing with Terahertz Radiation (Springer, 2010).
  2. M. Tonouchi, “Cutting-edge terahertz technology,” Nat. Photonics1(2), 97–105 (2007). [CrossRef]
  3. P. U. Jepsen, D. G. Cooke, and M. Koch, “Terahertz spectroscopy and imaging — Modern techniques and applications,” Laser Photonics Rev.5(1), 124–166 (2011). [CrossRef]
  4. A. J. Fitzgerald, E. Berry, N. N. Zinovev, G. C. Walker, M. A. Smith, and J. M. Chamberlain, “An introduction to medical imaging with coherent terahertz frequency radiation,” Phys. Med. Biol.47(7), R67–R84 (2002). [CrossRef] [PubMed]
  5. P. H. Siegel, “Terahertz Technology in Biology and medicine,” IEEE Trans. Microw. Theory Tech.52(10), 2438–2447 (2004). [CrossRef]
  6. G. J. Wilmink and J. E. Grundt, “Current State of Research on Biological Effects of Terahertz Radiation,” J. Infrared Millim. Terahz Waves32(10), 1074–1122 (2011). [CrossRef]
  7. A. G. Markelz, S. Whitmire, J. Hillebrecht, and R. Birge, “THz time domain spectroscopy of biomolecular conformational modes,” Phys. Med. Biol.47(21), 3797–3805 (2002). [CrossRef] [PubMed]
  8. B. M. Fischer, M. Walther, and P. U. Jepsen, “Far-infrared vibrational modes of DNA components studied by terahertz time-domain spectroscopy,” Phys. Med. Biol.47(21), 3807–3814 (2002). [CrossRef] [PubMed]
  9. M. Brucherseifer, M. Nagel, P. Haring Bolivar, H. Kurz, A. Bosserhoff, and R. Büttner, “Label-free probing of the binding state of DNA by time-domain terahertz sensing,” Appl. Phys. Lett.77(24), 4049–4051 (2000). [CrossRef]
  10. S. W. Smye, J. M. Chamberlain, A. J. Fitzgerald, and E. Berry, “The interaction between Terahertz radiation and biological tissue,” Phys. Med. Biol.46(9), R101–R112 (2001). [CrossRef] [PubMed]
  11. M. Nagel, P. Haring Bolivar, M. Brucherseifer, H. Kurz, A. Bosserhoff, and R. Büttner, “Integrated THz technology for label-free genetic diagnostics,” Appl. Phys. Lett.80(1), 154–156 (2002). [CrossRef]
  12. M. Vasudev, J. Yang, H.-S. Jung, M. A. Stroscio, and M. Dutta, “Integrated nanostructure–semiconductor molecular complexes as tools for THz spectral studies of DNA,” IEEE Sens. J.10(3), 524–530 (2010). [CrossRef]
  13. S. J. Kim, B. Born, M. Havenith, and M. Gruebele, “Real-time detection of protein-water dynamics upon protein folding by terahertz absorption spectroscopy,” Angew. Chem. Int. Ed. Engl.47(34), 6486–6489 (2008). [CrossRef] [PubMed]
  14. A. G. Markelz, “Terahertz Dielectric Sensitivity to Biomolecular Structure and Function,” IEEE J. Sel. Top. Quantum Electron.14(1), 180–190 (2008). [CrossRef]
  15. P. C. Ashworth, E. Pickwell-MacPherson, E. Provenzano, S. E. Pinder, A. D. Purushotham, M. Pepper, and V. P. Wallace, “Terahertz pulsed spectroscopy of freshly excised human breast cancer,” Opt. Express17(15), 12444–12454 (2009). [CrossRef] [PubMed]
  16. A. J. Fitzgerald, V. P. Wallace, M. Jimenez-Linan, L. Bobrow, R. J. Pye, A. D. Purushotham, and D. D. Arnone, “Terahertz pulsed imaging of human breast tumors,” Radiology239(2), 533–540 (2006). [CrossRef] [PubMed]
  17. R. M. Woodward, V. P. Wallace, D. D. Arnone, E. H. Linfield, and M. Pepper, “Terahertz pulsed imaging of skin cancer in the time and frequency domain,” J. Biol. Phys.29(2/3), 257–259 (2003). [CrossRef] [PubMed]
  18. P. C. Ashworth, P. O’Kelly, A. D. Purushotham, S. E. Pinder, M. Kontos, M. Pepper, and V. P. Wallace, “An intra-operative THz probe for use during the surgical removal of breast tumors,” in 33rd International Conference on Infrared, Millimeter and Terahertz Waves, 2008. IRMMW-THz 2008 (2008), pp. 1–3. doi: 10.1109/ICIMW.2008.4665810. [CrossRef]
  19. “TeraView receives MHRA approval to conduct in-vivo cancer imaging trials,” http://www.teraview.com/news/terahertz-news/TeraView-receives-in-vivo-trials-approval.html
  20. J. F. Federici, B. Schulkin, F. Huang, D. Gary, R. Barat, F. Oliveira, and D. Zimdars, “THz imaging and sensing for security applications: explosives, weapons and drugs,” Semicond. Sci. Technol.20(7), S266–S280 (2005). [CrossRef]
  21. D. Zimdars and J. S. White, “Terahertz reflection imaging for package and personnel inspection,” Proc. SPIE5411, 78–83 (2004). [CrossRef]
  22. B. S. Alexandrov, V. Gelev, A. R. Bishop, A. Usheva, and K. O. Rasmussen, “DNA breathing dynamics in the presence of a terahertz field,” Phys. Lett. A374(10), 1214–1217 (2010). [CrossRef] [PubMed]
  23. A. Korenstein-Ilan, A. Barbul, P. Hasin, A. Eliran, A. Gover, and R. Korenstein, “Terahertz radiation increases genomic instability in human lymphocytes,” Radiat. Res.170(2), 224–234 (2008). [CrossRef] [PubMed]
  24. H. Hintzsche, C. Jastrow, T. Kleine-Ostmann, H. Stopper, E. Schmid, and T. Schrader, “Terahertz radiation induces spindle disturbances in human-hamster hybrid cells,” Radiat. Res.175(5), 569–574 (2011). [CrossRef] [PubMed]
  25. G. J. Wilmink, B. L. Ibey, C. L. Roth, R. L. Vincelette, B. D. Rivest, C. B. Horn, J. Bernhard, D. Roberson, and W. P. Roach, “Determination of death thresholds and identification of terahertz (THz) – specific gene expression signatures,” Proc. SPIE7562, 75620K, 75620K-8 (2010). [CrossRef]
  26. G. J. Wilmink, B. D. Rivest, B. L. Ibey, C. L. Roth, J. Bernhard, and W. P. Roach, “Quantitative investigation of bioeffects associated with terahertz radiation,” Proc. SPIE7562, 75620L, 75620L-10 (2010). [CrossRef]
  27. J. Bock, Y. Fukuyo, S. Kang, M. L. Phipps, L. B. Alexandrov, K. Ø. Rasmussen, A. R. Bishop, E. D. Rosen, J. S. Martinez, H.-T. Chen, G. Rodriguez, B. S. Alexandrov, and A. Usheva, “Mammalian stem cells reprogramming in response to terahertz radiation,” PLoS ONE5(12), e15806 (2010). [CrossRef] [PubMed]
  28. B. S. Alexandrov, K. Ø. Rasmussen, A. R. Bishop, A. Usheva, L. B. Alexandrov, S. Chong, Y. Dagon, L. G. Booshehri, C. H. Mielke, M. L. Phipps, J. S. Martinez, H.-T. Chen, and G. Rodriguez, “Non-thermal effects of terahertz radiation on gene expression in mouse stem cells,” Biomed. Opt. Express2(9), 2679–2689 (2011). [CrossRef] [PubMed]
  29. E. Berry, G. C. Walker, A. J. Fitzgerald, N. N. Zinov’ev, M. Chamberlain, S. W. Smye, R. E. Miles, and M. A. Smith, “Do in vivo terahertz imaging systems comply with safety guidelines?” J. Laser Appl.15(3), 192–198 (2003). [CrossRef]
  30. T. T. L. Kristensen, W. Withayachumnankul, P. U. Jepsen, and D. Abbott, “Modeling terahertz heating effects on water,” Opt. Express18(5), 4727–4739 (2010). [CrossRef] [PubMed]
  31. S. M. Chitanvis, “Can low-power electromagnetic radiation disrupt hydrogen bonds in dsDNA?” J. Polym. Sci., B, Polym. Phys.44(18), 2740–2747 (2006). [CrossRef]
  32. W. Zhuang, Y. Feng, and E. W. Prohofsky, “Self-consistent calculation of localized DNA vibrational properties at a double-helix-single-strand junction with anharmonic potential,” Phys. Rev. A41(12), 7033–7042 (1990). [CrossRef] [PubMed]
  33. E. P. Rogakou, D. R. Pilch, A. H. Orr, V. S. Ivanova, and W. M. Bonner, “DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139,” J. Biol. Chem.273(10), 5858–5868 (1998). [CrossRef] [PubMed]
  34. O. A. Sedelnikova, D. R. Pilch, C. Redon, and W. M. Bonner, “Histone H2AX in DNA damage and repair,” Cancer Biol. Ther.2(3), 233–235 (2003). [CrossRef] [PubMed]
  35. F. Blanchard, G. Sharma, L. Razzari, X. Ropagnol, H.-C. Bandulet, F. Vidal, R. Morandotti, J.-C. Kieffer, T. Ozaki, H. Tiedje, H. Haugen, M. Reid, and F. A. Hegmann, “Generation of intense terahertz radiation via optical methods,” IEEE J. Sel. Top. Quantum Electron.17(1), 5–16 (2011). [CrossRef]
  36. M. C. Hoffmann and J. A. Fülöp, “Intense ultrashort terahertz pulses: generation and applications,” J. Phys. D Appl. Phys.44(8), 083001 (2011). [CrossRef]
  37. E. Boelsma, S. Gibbs, C. Faller, and M. Ponec, “Characterization and comparison of reconstructed skin models: morphological and immunohistochemical evaluation,” Acta Derm. Venereol.80(2), 82–88 (2000). [PubMed]
  38. O. A. Sedelnikova, A. Nakamura, O. Kovalchuk, I. Koturbash, S. A. Mitchell, S. A. Marino, D. J. Brenner, and W. M. Bonner, “DNA double-strand breaks form in bystander cells after microbeam irradiation of three-dimensional human tissue models,” Cancer Res.67(9), 4295–4302 (2007). [CrossRef] [PubMed]
  39. N. S. Agar, G. M. Halliday, R. S. Barnetson, H. N. Ananthaswamy, M. Wheeler, and A. M. Jones, “The basal layer in human squamous tumors harbors more UVA than UVB fingerprint mutations: a role for UVA in human skin carcinogenesis,” Proc. Natl. Acad. Sci. U.S.A.101(14), 4954–4959 (2004). [CrossRef] [PubMed]
  40. S. Q. Wang, R. Setlow, M. Berwick, D. Polsky, A. A. Marghoob, A. W. Kopf, and R. S. Bart, “Ultraviolet A and melanoma: a review,” J. Am. Acad. Dermatol.44(5), 837–846 (2001). [CrossRef] [PubMed]
  41. J. Cadet, E. Sage, and T. Douki, “Ultraviolet radiation-mediated damage to cellular DNA,” Mutat. Res.571(1-2), 3–17 (2005). [CrossRef] [PubMed]
  42. R. P. Rastogi, A. Richa, A. Kumar, M. B. Tyagi, and R. P. Sinha, “Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair,” J. Nucleic Acids2010, 592980 (2010). [CrossRef] [PubMed]
  43. O. Kovalchuk, F. J. Zemp, J. N. Filkowski, A. M. Altamirano, J. S. Dickey, G. Jenkins-Baker, S. A. Marino, D. J. Brenner, W. M. Bonner, and O. A. Sedelnikova, “microRNAome changes in bystander three-dimensional human tissue models suggest priming of apoptotic pathways,” Carcinogenesis31(10), 1882–1888 (2010). [CrossRef] [PubMed]
  44. J. H. J. Hoeijmakers, “Genome maintenance mechanisms for preventing cancer,” Nature411(6835), 366–374 (2001). [CrossRef] [PubMed]
  45. J. S. Dickey, F. J. Zemp, A. Altamirano, O. A. Sedelnikova, W. M. Bonner, and O. Kovalchuk, “H2AX phosphorylation in response to DNA double-strand break formation during bystander signalling: effect of microRNA knockdown,” Radiat. Prot. Dosimetry143(2-4), 264–269 (2011). [CrossRef] [PubMed]
  46. W. M. Bonner, C. E. Redon, J. S. Dickey, A. J. Nakamura, O. A. Sedelnikova, S. Solier, and Y. Pommier, “γH2AX and cancer,” Nat. Rev. Cancer8(12), 957–967 (2008). [CrossRef] [PubMed]
  47. H. T. Wang, B. Choi, and M. S. Tang, “Melanocytes are deficient in repair of oxidative DNA damage and UV-induced photoproducts,” Proc. Natl. Acad. Sci. U.S.A.107(27), 12180–12185 (2010). [CrossRef] [PubMed]
  48. J. Fillingham, M.-C. Keogh, and N. J. Krogan, “γH2AX and its role in DNA double-strand break repair,” Biochem. Cell Biol.84(4), 568–577 (2006). [CrossRef] [PubMed]
  49. P. McGlynn and R. G. Lloyd, “Recombinational repair and restart of damaged replication forks,” Nat. Rev. Mol. Cell Biol.3(11), 859–870 (2002). [CrossRef] [PubMed]
  50. K. K. Khanna and S. P. Jackson, “DNA double-strand breaks: signaling, repair and the cancer connection,” Nat. Genet.27(3), 247–254 (2001). [CrossRef] [PubMed]
  51. D. Menendez, A. Inga, and M. A. Resnick, “The expanding universe of p53 targets,” Nat. Rev. Cancer9(10), 724–737 (2009). [CrossRef] [PubMed]
  52. E. Bolderson, D. J. Richard, B. B. Zhou, and K. K. Khanna, “Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair,” Clin. Cancer Res.15(20), 6314–6320 (2009). [CrossRef] [PubMed]
  53. S. Seité, D. Moyal, M. P. Verdier, C. Hourseau, and A. Fourtanier, “Accumulated p53 protein and UVA protection level of sunscreens,” Photodermatol. Photoimmunol. Photomed.16(1), 3–9 (2000). [CrossRef] [PubMed]
  54. A. Krones-Herzig, S. Mittal, K. Yule, H. Liang, C. English, R. Urcis, T. Soni, E. D. Adamson, and D. Mercola, “Early growth response 1 acts as a tumor suppressor in vivo and in vitro via regulation of p53,” Cancer Res.65(12), 5133–5143 (2005). [CrossRef] [PubMed]
  55. Y. Zwang, A. Sas-Chen, Y. Drier, T. Shay, R. Avraham, M. Lauriola, E. Shema, E. Lidor-Nili, J. Jacob-Hirsch, N. Amariglio, Y. Lu, G. B. Mills, G. Rechavi, M. Oren, E. Domany, and Y. Yarden, “Two phases of mitogenic signaling unveil roles for p53 and EGR1 in elimination of inconsistent growth signals,” Mol. Cell42(4), 524–535 (2011). [CrossRef] [PubMed]
  56. B. L. Mahaney, K. Meek, and S. P. Lees-Miller, “Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining,” Biochem. J.417(3), 639–650 (2009). [CrossRef] [PubMed]
  57. P. Reynolds, J. A. Anderson, J. V. Harper, M. A. Hill, S. W. Botchway, A. W. Parker, and P. O’Neill, “The dynamics of Ku70/80 and DNA-PKcs at DSBs induced by ionizing radiation is dependent on the complexity of damage,” Nucleic Acids Res.40(21), 10821–10831 (2012). [CrossRef] [PubMed]
  58. H. Chen, Y. Bao, L. Yu, R. Jia, W. Cheng, and C. Shao, “Comparison of cellular damage response to low-dose-rate 125I seed irradiation and high-dose-rate gamma irradiation in human lung cancer cells,” Brachytherapy11(2), 149–156 (2012). [CrossRef] [PubMed]
  59. C. J. Sherr and J. M. Roberts, “Inhibitors of mammalian G1 cyclin-dependent kinases,” Genes Dev.9(10), 1149–1163 (1995). [CrossRef] [PubMed]
  60. T. Sperka, J. Wang, and K. L. Rudolph, “DNA damage checkpoints in stem cells, ageing and cancer,” Nat. Rev. Mol. Cell Biol.13(9), 579–590 (2012). [CrossRef] [PubMed]

Cited By

Alert me when this paper is cited

OSA is able to provide readers links to articles that cite this paper by participating in CrossRef's Cited-By Linking service. CrossRef includes content from more than 3000 publishers and societies. In addition to listing OSA journal articles that cite this paper, citing articles from other participating publishers will also be listed.


Fig. 1 Fig. 2 Fig. 3
Fig. 4

« Previous Article  |  Next Article »

OSA is a member of CrossRef.

CrossCheck Deposited