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Polymorphic radiation sensitivity of human natural killer activity: possible role of DNA strand breakage
Abstract:
Natural killer (NK) activity of human mononuclear cells is sensitive to inhibition by radiation, under the control of polymorphic X linked genes. In order to define the mechanism of this inhibition, we have evaluated the ability of treatments known to damage DNA to inhibit NK activity. The alkylating agents streptozotocin (SZ) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were potent inhibitors of NK activity. Further, a specific competitive inhibitor of adenosine diphosphoribosyl polymerase (ADPRP), 3-aminobenzamide, was able to prevent inhibition by gamma-radiation, UV radiation, and the two alkylating drugs, SZ and MNNG, suggesting the ADPRP, known to be activated by DNA strand breakage, mediates the inhibition by these treatments. NK activity of radioresistant subjects was somewhat more resistant to inhibition by SZ or UVR when compared to radiosensitive NK activity but neither of these treatments gave the clear phenotypic distinction of gamma-radiation, suggesting that chemical strand breakage does not precisely model gamma-radiation and also that the mechanism of UVR inhibition may differ from that of gamma-radiation. These results indicate a role for activation of ADPRP in the inhibitory effect of UV and gamma-radiation on human NK activity and suggest that the biochemical basis for polymorphism in the sensitivity of NK activity to gamma-radiation will be found in the sensitivity to ADPRP activation or the level of activation of this enzyme, known to be the key to DNA repair.
Insights
DNA damage inhibits natural killer (NK) cell activity via adenosine diphosphoribosyl polymerase (ADPRP). This enzyme’s activation explains radiation sensitivity variations in NK cells, impacting DNA repair.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Natural killer (NK) cell activity is modulated by DNA-damaging agents and linked to polymorphic X-linked genes.
- Understanding the mechanism of radiation-induced NK cell inhibition is crucial for immunological research.
Purpose of the Study:
- To elucidate the mechanism by which DNA-damaging treatments inhibit human NK cell activity.
- To investigate the role of adenosine diphosphoribosyl polymerase (ADPRP) in mediating this inhibition.
Main Methods:
- Evaluating the inhibitory effects of alkylating agents (streptozotocin, MNNG) and radiation (gamma, UV) on NK activity.
- Assessing the impact of an ADPRP inhibitor (3-aminobenzamide) on NK cell responses to these treatments.
- Comparing NK activity inhibition in radioresistant versus radiosensitive subjects.
Main Results:
- Alkylating agents streptozotocin (SZ) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) potently inhibited NK activity.
- 3-aminobenzamide prevented inhibition by gamma-radiation, UV radiation, SZ, and MNNG, implicating ADPRP activation.
- While NK activity in radioresistant subjects showed some resistance to SZ and UV, gamma-radiation provided a clearer distinction, suggesting differing mechanisms.
Conclusions:
- ADPRP activation plays a significant role in the inhibition of human NK activity by UV and gamma radiation.
- Polymorphisms in NK cell sensitivity to gamma-radiation likely stem from variations in ADPRP activation sensitivity or levels.
- ADPRP is a key enzyme in DNA repair, and its activation mediates radiation-induced NK cell inhibition.