Repair of HZE-particle-induced DNA double-strand breaks in normal human fibroblasts

Aroumougame Asaithamby, Naoya Uematsu, Aloke Chatterjee, Michael D. Story, Sandeep Burma, David J. Chen

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

DNA damage generated by high-energy and high-Z (HZE) particles is more skewed toward multiply damaged sites or clustered DNA damage than damage induced by low-linear energy transfer (LET) X and γ rays. Clustered DNA damage includes abasic sites, base damages and single- (SSBs) and double-strand breaks (DSBs). This complex DNA damage is difficult to repair and may require coordinated recruitment of multiple DNA repair factors. As a consequence of the production of irreparable clustered lesions, a greater biological effectiveness is observed for HZE-particle radiation than for low-LET radiation. To understand how the inability of cells to rejoin DSBs contributes to the greater biological effectiveness of HZE particles, the kinetics of DSB rejoining and cell survival after exposure of normal human skin fibroblasts to a spectrum of HZE particles was examined. Using γ-H2AX as a surrogate marker for DSB formation and rejoining, the ability of cells to rejoin DSBs was found to decrease with increasing Z; specifically, iron-ion-induced DSBs were repaired at a rate similar to those induced by silicon ions, oxygen ions and γ radiation, but a larger fraction of iron-ion-induced damage was irreparable. Furthermore, both DNA-PKcs (DSB repair factor) and 53BP1 (DSB sensing protein) co-localized with γ-H2AX along the track of dense ionization produced by iron and silicon ions and their focus dissolution kinetics was similar to that of γ-H2AX. Spatial co-localization analysis showed that unlike γ-H2AX and 53BP1, phosphorylated DNA-PKcs was localized only at very specific regions, presumably representing the sites of DSBs within the tracks. Examination of cell survival by clonogenic assay indicated that cell killing was greater for iron ions than for silicon and oxygen ions and γ rays. Collectively, these data demonstrate that the inability of cells to rejoin DSBs within clustered DNA lesions likely contributes to the greater biological effectiveness of HZE particles.

Original languageEnglish (US)
Pages (from-to)437-446
Number of pages10
JournalRadiation Research
Volume169
Issue number4
DOIs
StatePublished - Apr 2008

Fingerprint

Cosmic Radiation
Double-Stranded DNA Breaks
fibroblasts
strands
deoxyribonucleic acid
Fibroblasts
Ions
ions
DNA damage
DNA
DNA Damage
damage
Silicon
silicon
Iron
iron
Linear Energy Transfer
Radiation
energy transfer
lesions (animal)

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Radiology Nuclear Medicine and imaging
  • Biophysics
  • Radiation

Cite this

Repair of HZE-particle-induced DNA double-strand breaks in normal human fibroblasts. / Asaithamby, Aroumougame; Uematsu, Naoya; Chatterjee, Aloke; Story, Michael D.; Burma, Sandeep; Chen, David J.

In: Radiation Research, Vol. 169, No. 4, 04.2008, p. 437-446.

Research output: Contribution to journalArticle

Asaithamby, Aroumougame ; Uematsu, Naoya ; Chatterjee, Aloke ; Story, Michael D. ; Burma, Sandeep ; Chen, David J. / Repair of HZE-particle-induced DNA double-strand breaks in normal human fibroblasts. In: Radiation Research. 2008 ; Vol. 169, No. 4. pp. 437-446.
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