Differences in Phosphorylated Histone H2AX Foci Formation and Removal of Cells Exposed to Low and High Linear Energy Transfer Radiation

Abstract

The use of particle ion beams in cancer radiotherapy has a long history. Today, beams of protons or heavy ions, predominantly carbon ions, can be accelerated to precisely calculated energies which can be accurately targeted to tumors. This particle therapy works by damaging the DNA of tissue cells, ultimately causing their death. Among the different types of DNA lesions, the formation of DNA double strand breaks is considered to be the most relevant of deleterious damages of ionizing radiation in cells. It is well-known that the extremely large localized energy deposition can lead to complex types of DNA double strand breaks. These effects can lead to cell death, mutations, genomic instability, or carcinogenesis. Complex double strand breaks can increase the probability of mis-rejoining by NHEJ. As a consequence differences in the repair kinetics following high and low LET irradiation qualities are attributed mainly to quantitative differences in their contributions of the fast and slow repair component. In general, there is a higher contribution of the slow component of DNA double strand repair after exposure to high LET radiation, which is thought to reflect the increased amount of complex DNA double strand breaks. These can be accurately measured by the γ-H2AX assay, because the number of phosphorylated H2AX foci correlates well with the number of double strand breaks induced by low or / and high LET radiation.

Mesenchymal stem cells are resistant to carbon ion radiotherapy

“…MSCs were able to efficiently repair these critical DNA lesions both after photon and after carbon ion irradiation as assessed by γH2AX immunostaining. While these cells exhibited less γH2AX foci directly after exposure to particle radiation than after photon treatment, carbon ion-induced foci appeared bigger; this finding corresponds to previously published data suggesting larger foci sizes along carbon ion tracks due to the increased creation of clustered DNA damage by densely ionizing particle radiation [ 19 ]. The ability of MSCs to swiftly repair both photon and particle-induced DNA double strand breaks was also reflected by the activation of the ataxia teleangiectasia-mutated (ATM)-dependent DNA damage signaling pathway.…”

Unsolved mystery: the role of BRCA1 in DNA end-joining

“…One study showed that extracts derived from BRCA1-null MEFs exhibit significantly reduced end-joining activity compared with MEFs with wild-type BRCA1, providing initial insight into BRCA1's function in C-NHEJ [ 33 ]. Similarly, whole-cell extracts from the human BRCA1 -defective cell line HCC1937 had significantly reduced C-NHEJ activity compared with control cell extracts [ 34 ]. However, a number of studies suggest that BRCA1 is not required for C-NHEJ.…”

Heavy Ion Beams for Radiobiology: Dosimetry and Nanodosimetry at HIL

“…High LET radiation induces complex DNA damage, a class of DNA lesions that includes two or more individual types of lesions within one or two helical turns of the DNA [16]. DNA sensing proteins localize to the sites of DNA DSB resulting in the formation of microscopically visible nuclear domains referred to as radiation-induced foci in the γ-H2AX assay [17].…”