Characterization of a complex¹²⁵I-induced DNA double-strand break: Implications for repair

Abstract

125I-TFO-induced DSBs exhibit a high degree of base damage clustering proximal to the DSB end. At least 60% of the nucleotides within 10 bp of the 125I decay site are sensitive to cleavage by endo IV, endo III, or Fpg following damage accumulation in the presence of DMSO, whereas > or = 80% are sensitive in the absence of DMSO. The high degree of base damage clustering associated with the 125I-TFO-induced DSB end may be a major factor leading to its negligible in vitro repair by the non-homologous end-joining pathway (NHEJ).

The Ku heterodimer: Function in DNA repair and beyond

“…Indeed there is also some evidence that high complexity DSBs (containing single-strand overhangs, base oxidation and abasic sites) are repaired with slow kinetics and are dependent on DNA-PK CS activity, while low complexity DSBs (without surrounding DNA junction, which is later cut to resolve the chromosome. damage) do not require DNA-PK CS binding, and are efficiently ligated with only Ku and the ligation complex [80][81][82][83].…”

Nonhomologous end joining of complex DNA double-strand breaks with proximal thymine glycol and interplay with base excision repair

“…Datta et al [7,40,41] also examined the molecular structure as well as repairability of site-specific DSBs induced by an 125 I-labeled triplex-forming oligonucleotide, as a model of high-LET radiation. Proximal base lesions (i.e., glycosylase-sensitive sites) were detected in at least 50% of each strand in the vicinity of the DSB, and a comparable number of abasic sites (E. coli endonuclease IV-sensitive sites) were detected as well.…”

Auger processes in the 21st century

“…The nature of the DNA damage caused by 125 I decays has recently been studied by producing site-specific radiation-induced DSB in plasmid DNA by triplex forming oligonucleotide (TFO) targeted 125 I (Datta et al 2005a, 2005b, 2006). This approach enables precise delivery of 125 I to a specific predetermined location on the DNA.…”

“…The present generation of theoretical modeling of DNA damage caused by Auger processes is the result of an evolution that has occurred over more than 20 years. New capabilities in the realm of biological assays, such as those of Datta et al (2005a, 2005b, 2006), will require that the models continue to evolve. Among the many aspects that are considered by the modelers are the stochastics of the number of decays per plasmid, electron cross sections for low energy electrons in water and in DNA, stochastics of the Auger electron spectra, direct effects of the electrons, indirect effects of radical species produced via radiolysis of water, charge transfer, charge neutralization, and the effect of molecular structure on all of the above.…”