December 22, 2011

DNA Repair Mechanism works much better at low radiation doses so damage is not linear without threshhold

1. Researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab), through a combination of time-lapse live imaging and mathematical modeling of a special line of human breast cells, have found evidence to suggest that for low dose levels of ionizing radiation, cancer risks may not be directly proportional to dose. This contradicts the standard model for predicting biological damage from ionizing radiation – the linear-no-threshold hypothesis or LNT – which holds that risk is directly proportional to dose at all levels of irradiation.

Our data show that at lower doses of ionizing radiation, DNA repair mechanisms work much better than at higher doses,” says Mina Bissell, a world-renowned breast cancer researcher with Berkeley Lab’s Life Sciences Division. “This non-linear DNA damage response casts doubt on the general assumption that any amount of ionizing radiation is harmful and additive.”


Imaging of a cell’s DNA damage response to radiation shows that 1.5 minutes after irradiation, the sizes and intensities of radiation induced foci (RIF) are small and weak, but 30 minutes later damage sites have clustered into larger and brighter RIF, probably reflecting DNA repair centers.

PNAS - Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells



“We hypothesize that contrary to what has long been thought, double strand breaks are not static entities but will rapidly cluster into preferred regions of the nucleus we call DNA repair centers as radiation exposure increases,” says Costes. “As a result of this clustering, a single RIF may reflect a center where multiple double strand breaks are rejoined. Such multiple repair activity increases the risks of broken DNA strands being incorrectly rejoined and that can lead to cancer.”

The concept of DNA “repair centers” and the meaning of radiation-induced foci (RIF) in human cells have remained controversial. RIFs are characterized by the local recruitment of DNA damage sensing proteins such as p53 binding protein (53BP1). Here, we provide strong evidence for the existence of repair centers. We used live imaging and mathematical fitting of RIF kinetics to show that RIF induction rate increases with increasing radiation dose, whereas the rate at which RIFs disappear decreases. We show that multiple DNA double-strand breaks (DSBs) 1 to 2 μm apart can rapidly cluster into repair centers. Correcting mathematically for the dose dependence of induction/resolution rates, we observe an absolute RIF yield that is surprisingly much smaller at higher doses: 15 RIF/Gy after 2 Gy exposure compared to approximately 64 RIF/Gy after 0.1 Gy. Cumulative RIF counts from time lapse of 53BP1-GFP in human breast cells confirmed these results. The standard model currently in use applies a linear scale, extrapolating cancer risk from high doses to low doses of ionizing radiation. However, our discovery of DSB clustering over such large distances casts considerable doubts on the general assumption that risk to ionizing radiation is proportional to dose, and instead provides a mechanism that could more accurately address risk dose dependency of ionizing radiation.

8 pages of supplemental information

2. A provocative new study released this week suggests as many as 14,000 Americans may have died as a result of exposure to radioactive particles blown here from Japan after the Fukushima nuclear reactor meltdown in March. But even though the report is gaining some attention, experts say there is no scientific basis for its claims.

Cancers typically associated with lower levels of radiation take years to develop, Maidment explained. “With leukemia, you’re talking about five to seven years,” he said. “And there’s a 10 to 20 year delay for solid tumors. I know of no mechanism that could get you instantaneous mortality from radiation at lower levels.”

Dr. Robert L. Brent agreed. “The exposure of the USA population was extremely small and could not account for any acute lethal effects of radiation,” said Brent, a member of the National Counsel for Radiation Protection and distinguished professor of pediatrics, radiology and pathology at the Jefferson Medical College and the Dupont Hospital for Children.

"The authors indicated that SIDS (Sudden Infant Death Syndrome) was increased according to the mortality figures the authors obtained from the CDC," said Brent. "To infer that SIDS can be produced by low or high exposures to protracted radiation is naïve. That is not even a remote possibility."

So, how can you explain the rise in U.S. deaths following the reactor disaster?

There’s something called biological variability, Brent said. “For example, if you look at reports from the CDC on birth defects, you might find in a particular month a single case of Down Syndrome. The next month there might be seven. That’s biological variability.”

You can’t assume that a bump in the death rate was caused by a particular factor just because the timing was right, Brent said. “It has to be biologically plausible before you think about linking the two.”

Some associations are just the result of chance, experts said.


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