05/01/2012
Cell-Cycle Checkpoint Control Exhibits Nonlinear Behavior at Low Radiation Doses
The Science
When cells are exposed to a radiation dose large enough to cause chromosome aberrations, they are normally arrested at the G2/M checkpoint, which facilitates DNA repair. New research confirms an activation threshold for the G2/M cell-cycle checkpoint, hinting at two separate radiation response mechanisms that act below and above this threshold. When arrest kinetics were monitored in mouse embryo fibroblasts over a range of low doses and time, no significant checkpoint activation was observed at doses below 100 mGy. The checkpoint is only fully activated at doses where most of the cells are either bound for mitotic catastrophe or are reproductively dead. Parallel measurements done with cells haplo-insufficient for one or more radioresistance genes showed similar checkpoint activation kinetics. This is in contrast to previous work showing that haplo-insufficiency for several radioresistance genes imparts intermediate phenotypes for endpoints including apoptosis, transformation, and sRadiation protection standards, as set forth by a host of regulatory bodies, are based on the uniformity of response of the human population to radiation, and a completely linear relationship between cancer incidence and absorbed dose.urvival. These findings suggest that checkpoint control does not contribute toward these intermediate phenotypes and that different biological processes can be activated at high doses compared to low doses. The journal selected the first author, Erik Young, for its Editors’ Award to a Radiation Research Society Scholar-in-Training as the best paper of the last year.
Summary
Radiation protection standards, as set forth by a host of regulatory bodies, are based on the uniformity of response of the human population to radiation, and a completely linear relationship between cancer incidence and absorbed dose. A gathering body of evidence has begun to accrue in support of two separate radiation response biologies: one response program functioning at higher doses, and a separate response program functioning at lower doses. Determination of cancer incidence in response to radiation at lower doses is further confounded by known variation in the sensitivity of humans to radiation. Increases in radiosensitivity are associated with homozygous loss of function mutations in genes associated with tumor suppression, DNA repair and DNA damage sensing.
BER Program Manager
Resham Kulkarni
U.S. Department of Energy, Biological and Environmental Research (SC-33)
Biological Systems Science Division
[email protected]
References
Young, E. F., L. B. Smilenov, H. B., Lieberman, and E. J. Hall. 2012. “Combined Haplo-Insufficiency and Genetic Control of the G2/M Checkpoint in Irradiated Cells,” Radiation Research 177(6), 743-750. DOI:10.1667/RR2875.1.