Cellular response to ionizing radiation

Magda, D. et al. (2001) Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species, Int. J. Radiat. Oncol. Biol. 51, 1025-1036. 

Collins A. Cellular responses to ionizing radiation Effects of interrupting DNA repair with chemical agents. Int J Radiat Biol Relat Stud Phys Chem Med 1987 51 971-83. 

Thiamine alters the genetic response to cell injury to protect cells. TPP inhibits p53 DNA binding, and the thiamine inhibits intracellular p53 activity. Thiamine affects two p53-regulated cellular responses to ionizing radiation rereplication and apoptosis (McLure et al., 2004). Thiamine also interacts with NFkappaB. Diabetes induces NFkappaB and this induction is diminished by thiamine (Hammes et al., 2003). 

Figure 4. Outline of the cellular respose to ionizing radiation. 1.Early changes induced by radiation. 2. Adaptive response. 3. Initiation of apoptosis. 4. Execution of apoptosis. S. Late phases of apoptosis. The point of no return from death is the transition hum 3 to 4.

Further studies have implicated BRCAl in the cellular response to DNA double-stranded breaks (DSBs), a potentially lethal form of DNA damage. Cells defective in BRCAl possess numerous cytological and biological features that have been known for years to be correlated with perturbation in the maintenance of chromosome stability. This includes aneuploidy, centrosome amplification, spontaneous chromosome breakage, aberrant recombination events, sensitivity to ionizing radiation, and impaired cell cycle checkpoints. In addition, a variety of experiments have demonstrated roles for BRCAl in enforcing the GfM cell cycle transition, homologous recombination between sister chromatids, as well as the restart of stalled replication in S phase. 

Chalmers A, Johnston P, Woodcock M et al. PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation. Int J Radiat Oncol Biol Phys 2004 58(2) 410-9. 

DNA strand breaks, induced by exposure to chemicals or ionizing radiation stimulate poly(ADP-ribose) polymerase activity (1, 2). The resultant protein modifications have been postulated to comprise an important step in the DNA repair process (3). Inhibitors of the polymerase have been shown to sensitize human fibroblasts (4) and certain tumor cells (5) to ionizing radiation and to inhibit the repair of potentially lethal radiation injury (6, 7). That the response of the tumor cell lines vary, with some showing sensitivity to inhibitors of poly(ADP-ribosyl)ation and irradiation while others do not, suggested a need for detailed investigation of the ADP-ribosylation process in these tumor cell lines. In the present study we report the quantitative variations in protein-bound mono(ADP-ribose) levels as well as poly(ADP-ribose) pol)unerase activities and cellular NAD levels of various tumor cells. To this end, we also describe die development and characterization of polyclonal antisera to mono(ADP-ribose) and its potential use as a probe for studies of ADP-ribosylation. 

Stiff T, O Driscoll M, Rief N et al (2004) ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res 64 2390-2396 Stucki M, Clapperton JA, Mohammad D et al (2005) MDCl directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 123 1213-1226... 

There is not room here to discuss the detailed mechanisms by which exposure to radiation causes adverse responses. Much of the effects of radiation result from its interaction with water to produce active species that include superoxide (Oi), hydroxyl radical (HO-), hydroperoxyl radical (HOO), and hydrogen peroxide (H202). These species oxidize cellular macromolecules. When DNA is so affected, mutagenesis and carcinogenesis may result. Ionizing radiation can also interact with organic substances to produce a carbonium ion, such as +CH3, that can alkylate nitrogenous bases on DNA. 

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