Modulation of the DNA-damage response to HZE particles by shielding

Bipasha Mukherjee, Cristel Vanessa Camacho, Nozomi Tomimatsu, Jack Miller, Sandeep Burma

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Ions of high atomic number and energy (HZE particles) pose a significant cancer risk to astronauts on prolonged space missions. On Earth, similar ions are being used for targeted cancer therapy. The properties of these particles can be drastically altered during passage through spacecraft shielding, therapy beam modulators, or the human body. Here, we have used pertinent responses to DNA double-strand breaks (DSBs) to understand the consequences of energy loss versus nuclear fragmentation of Fe ions during passage through shielding or tissue-equivalent materials. Phosphorylation of histone H2AX and recruitment of 53BP1 were used to generate 3D reconstructions of DNA damage in human cells and to follow its repair. Human cells are unable to repair a significant portion of DNA damage induced by Fe ions. DNA-PK and ATM are required, to different extents, for the partial repair of Fe-induced DNA damage. Aluminum shielding has little effect on DNA damage or its repair, confirming that the hulls of the Space Shuttle and the International Space Station afford scant protection against these particles. Lead shielding, on the other hand, exacerbates the effects of Fe ions due to energy loss during particle traversal. In sharp contrast, polyethylene (PE), a favored hydrogenous shield, results in DNA damage that is more amenable to repair presumably due to Fe-ion fragmentation. Human cells are indeed able to efficiently repair DSBs induced by chlorine ions and protons that represent fragmentation products of Fe. Interestingly, activation of the tumor suppressor p53 in Fe-irradiated cells is uniquely biphasic and culminates in the induction of high levels of p21 (Waf1/Cip1), p16 (INK4a) and senescence-associated β-galactosidase activity. Surprisingly, these events occur even in the absence of ATM kinase implying that ATR may be a major responder to the complex DNA damage inflicted by Fe ions. Significantly, fragmentation of the Fe beam through PE attenuates these responses and this, in turn, results in better long-term survival in a colony-forming assay. Our results help us to understand the biological consequences of ion fragmentation through materials, whether in space or in the clinic, and provide us with a biological basis for the use of hydrogenous materials like PE as effective space shields.

Original languageEnglish (US)
Pages (from-to)1717-1730
Number of pages14
JournalDNA Repair
Volume7
Issue number10
DOIs
StatePublished - Oct 1 2008

Fingerprint

Cosmic Radiation
Shielding
DNA Damage
Modulation
Ions
DNA
Repair
Polyethylene
Cells
Automatic teller machines
Energy dissipation
Spacecraft
Galactosidases
Astronauts
Nuclear Energy
Neoplasms
Phosphorylation
Double-Stranded DNA Breaks
Chlorine
Space shuttles

Keywords

  • ATM
  • ATR
  • DNA double-strand break (DSB)
  • DNA-damage response (DDR)
  • DNA-PK
  • H2AX
  • High-LET radiation
  • HZE particles
  • p53

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Mukherjee, B., Camacho, C. V., Tomimatsu, N., Miller, J., & Burma, S. (2008). Modulation of the DNA-damage response to HZE particles by shielding. DNA Repair, 7(10), 1717-1730. https://doi.org/10.1016/j.dnarep.2008.06.016

Modulation of the DNA-damage response to HZE particles by shielding. / Mukherjee, Bipasha; Camacho, Cristel Vanessa; Tomimatsu, Nozomi; Miller, Jack; Burma, Sandeep.

In: DNA Repair, Vol. 7, No. 10, 01.10.2008, p. 1717-1730.

Research output: Contribution to journalArticle

Mukherjee, B, Camacho, CV, Tomimatsu, N, Miller, J & Burma, S 2008, 'Modulation of the DNA-damage response to HZE particles by shielding', DNA Repair, vol. 7, no. 10, pp. 1717-1730. https://doi.org/10.1016/j.dnarep.2008.06.016
Mukherjee B, Camacho CV, Tomimatsu N, Miller J, Burma S. Modulation of the DNA-damage response to HZE particles by shielding. DNA Repair. 2008 Oct 1;7(10):1717-1730. https://doi.org/10.1016/j.dnarep.2008.06.016
Mukherjee, Bipasha ; Camacho, Cristel Vanessa ; Tomimatsu, Nozomi ; Miller, Jack ; Burma, Sandeep. / Modulation of the DNA-damage response to HZE particles by shielding. In: DNA Repair. 2008 ; Vol. 7, No. 10. pp. 1717-1730.
@article{14330ba94d95433a92a5c5acf4b69fbc,
title = "Modulation of the DNA-damage response to HZE particles by shielding",
abstract = "Ions of high atomic number and energy (HZE particles) pose a significant cancer risk to astronauts on prolonged space missions. On Earth, similar ions are being used for targeted cancer therapy. The properties of these particles can be drastically altered during passage through spacecraft shielding, therapy beam modulators, or the human body. Here, we have used pertinent responses to DNA double-strand breaks (DSBs) to understand the consequences of energy loss versus nuclear fragmentation of Fe ions during passage through shielding or tissue-equivalent materials. Phosphorylation of histone H2AX and recruitment of 53BP1 were used to generate 3D reconstructions of DNA damage in human cells and to follow its repair. Human cells are unable to repair a significant portion of DNA damage induced by Fe ions. DNA-PK and ATM are required, to different extents, for the partial repair of Fe-induced DNA damage. Aluminum shielding has little effect on DNA damage or its repair, confirming that the hulls of the Space Shuttle and the International Space Station afford scant protection against these particles. Lead shielding, on the other hand, exacerbates the effects of Fe ions due to energy loss during particle traversal. In sharp contrast, polyethylene (PE), a favored hydrogenous shield, results in DNA damage that is more amenable to repair presumably due to Fe-ion fragmentation. Human cells are indeed able to efficiently repair DSBs induced by chlorine ions and protons that represent fragmentation products of Fe. Interestingly, activation of the tumor suppressor p53 in Fe-irradiated cells is uniquely biphasic and culminates in the induction of high levels of p21 (Waf1/Cip1), p16 (INK4a) and senescence-associated β-galactosidase activity. Surprisingly, these events occur even in the absence of ATM kinase implying that ATR may be a major responder to the complex DNA damage inflicted by Fe ions. Significantly, fragmentation of the Fe beam through PE attenuates these responses and this, in turn, results in better long-term survival in a colony-forming assay. Our results help us to understand the biological consequences of ion fragmentation through materials, whether in space or in the clinic, and provide us with a biological basis for the use of hydrogenous materials like PE as effective space shields.",
keywords = "ATM, ATR, DNA double-strand break (DSB), DNA-damage response (DDR), DNA-PK, H2AX, High-LET radiation, HZE particles, p53",
author = "Bipasha Mukherjee and Camacho, {Cristel Vanessa} and Nozomi Tomimatsu and Jack Miller and Sandeep Burma",
year = "2008",
month = "10",
day = "1",
doi = "10.1016/j.dnarep.2008.06.016",
language = "English (US)",
volume = "7",
pages = "1717--1730",
journal = "DNA Repair",
issn = "1568-7864",
publisher = "Elsevier",
number = "10",

}

TY - JOUR

T1 - Modulation of the DNA-damage response to HZE particles by shielding

AU - Mukherjee, Bipasha

AU - Camacho, Cristel Vanessa

AU - Tomimatsu, Nozomi

AU - Miller, Jack

AU - Burma, Sandeep

PY - 2008/10/1

Y1 - 2008/10/1

N2 - Ions of high atomic number and energy (HZE particles) pose a significant cancer risk to astronauts on prolonged space missions. On Earth, similar ions are being used for targeted cancer therapy. The properties of these particles can be drastically altered during passage through spacecraft shielding, therapy beam modulators, or the human body. Here, we have used pertinent responses to DNA double-strand breaks (DSBs) to understand the consequences of energy loss versus nuclear fragmentation of Fe ions during passage through shielding or tissue-equivalent materials. Phosphorylation of histone H2AX and recruitment of 53BP1 were used to generate 3D reconstructions of DNA damage in human cells and to follow its repair. Human cells are unable to repair a significant portion of DNA damage induced by Fe ions. DNA-PK and ATM are required, to different extents, for the partial repair of Fe-induced DNA damage. Aluminum shielding has little effect on DNA damage or its repair, confirming that the hulls of the Space Shuttle and the International Space Station afford scant protection against these particles. Lead shielding, on the other hand, exacerbates the effects of Fe ions due to energy loss during particle traversal. In sharp contrast, polyethylene (PE), a favored hydrogenous shield, results in DNA damage that is more amenable to repair presumably due to Fe-ion fragmentation. Human cells are indeed able to efficiently repair DSBs induced by chlorine ions and protons that represent fragmentation products of Fe. Interestingly, activation of the tumor suppressor p53 in Fe-irradiated cells is uniquely biphasic and culminates in the induction of high levels of p21 (Waf1/Cip1), p16 (INK4a) and senescence-associated β-galactosidase activity. Surprisingly, these events occur even in the absence of ATM kinase implying that ATR may be a major responder to the complex DNA damage inflicted by Fe ions. Significantly, fragmentation of the Fe beam through PE attenuates these responses and this, in turn, results in better long-term survival in a colony-forming assay. Our results help us to understand the biological consequences of ion fragmentation through materials, whether in space or in the clinic, and provide us with a biological basis for the use of hydrogenous materials like PE as effective space shields.

AB - Ions of high atomic number and energy (HZE particles) pose a significant cancer risk to astronauts on prolonged space missions. On Earth, similar ions are being used for targeted cancer therapy. The properties of these particles can be drastically altered during passage through spacecraft shielding, therapy beam modulators, or the human body. Here, we have used pertinent responses to DNA double-strand breaks (DSBs) to understand the consequences of energy loss versus nuclear fragmentation of Fe ions during passage through shielding or tissue-equivalent materials. Phosphorylation of histone H2AX and recruitment of 53BP1 were used to generate 3D reconstructions of DNA damage in human cells and to follow its repair. Human cells are unable to repair a significant portion of DNA damage induced by Fe ions. DNA-PK and ATM are required, to different extents, for the partial repair of Fe-induced DNA damage. Aluminum shielding has little effect on DNA damage or its repair, confirming that the hulls of the Space Shuttle and the International Space Station afford scant protection against these particles. Lead shielding, on the other hand, exacerbates the effects of Fe ions due to energy loss during particle traversal. In sharp contrast, polyethylene (PE), a favored hydrogenous shield, results in DNA damage that is more amenable to repair presumably due to Fe-ion fragmentation. Human cells are indeed able to efficiently repair DSBs induced by chlorine ions and protons that represent fragmentation products of Fe. Interestingly, activation of the tumor suppressor p53 in Fe-irradiated cells is uniquely biphasic and culminates in the induction of high levels of p21 (Waf1/Cip1), p16 (INK4a) and senescence-associated β-galactosidase activity. Surprisingly, these events occur even in the absence of ATM kinase implying that ATR may be a major responder to the complex DNA damage inflicted by Fe ions. Significantly, fragmentation of the Fe beam through PE attenuates these responses and this, in turn, results in better long-term survival in a colony-forming assay. Our results help us to understand the biological consequences of ion fragmentation through materials, whether in space or in the clinic, and provide us with a biological basis for the use of hydrogenous materials like PE as effective space shields.

KW - ATM

KW - ATR

KW - DNA double-strand break (DSB)

KW - DNA-damage response (DDR)

KW - DNA-PK

KW - H2AX

KW - High-LET radiation

KW - HZE particles

KW - p53

UR - http://www.scopus.com/inward/record.url?scp=52049125006&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=52049125006&partnerID=8YFLogxK

U2 - 10.1016/j.dnarep.2008.06.016

DO - 10.1016/j.dnarep.2008.06.016

M3 - Article

C2 - 18672098

AN - SCOPUS:52049125006

VL - 7

SP - 1717

EP - 1730

JO - DNA Repair

JF - DNA Repair

SN - 1568-7864

IS - 10

ER -