Genes for Radiation Sensitivity

Published by Howard Hughes Medical Institute on April 06, 2009  :

HHMI researchers have identified a group of genes that influence a person's sensitivity to radiation. The findings are a step toward a long term goal of developing new tests that would help physicians determine the optimal dosage of radiation for cancer treatment based on a person's genetic profile.

• "This study identifies a set of genetic variants that influence how a cell responds to radiation induced damage," said Vivian G Cheung.
• "Now that we know these genetic variations, we hope to build predictors that tell us who is more sensitive to radiation, so that we can decrease dose of radiation therapy to avoid damaging normal tissue," said Cheung an HHMI investigator at the Children's Hospital of Pennsylvania and the University of Pennsylvania. Cheung  who is physician-scientist, was interested in how ionizing radiation induces damage in DNA, she said she was surprised that so little is know about why people differ in the amount of damage they sustain when exposed to radiation.
• Cheung and colleagues used human cell lines as proxies, exposing them to a standard radiation dose and noting which cells survived and which was killed. The cell lines had been previously developed from cells  collected from 15 families in Utah and represented about 150 individuals with well documented pedigrees.
• The scientists used microarrays designed to analyze the activity of more than 10,000 genes to take snapshots of gene expression in the cells prior to radiation exposure, and at two and six hours after exposure. After those studies, the researchers narrowed their focus to 3,280 genes whose expression went up or down by at least 50 percent.
• Among those genes, some were already know to have roles in repairing DNA damage, regulating the cell cycle or apoptosis.
• Each pattern of gene expression change in an individual's cells represented an inborn "phenotype", indicating sensitivity to radiation. In experiment the sensitivity was a function of whether the cell survived or were killed by the dose of radiation
• The radiation-response genes the team identified had been catalogued in the Human Genome Project, so their locatiions within the genome were known. But the activity of each gene was controlled by a switch-like bit of regulatory DNA. Variation in these regulatory sequences accounted for the differences in radiation response from one person to another.
•  The location of these regulators were not know.Researcher knew that some of the sequence might be within the genes themselves whereas others could be nearby or even on another chromosome.
  
• Using computational analysis, the scientists identified more than 1,250 phenotypes that segregated in certain families, however the locations were not pinpoints but long stretches of genetic material. To narrow down the search further they used " text mining".
• In addition, the team also used RNA interference to turn down the gene regulators.
• Cheung and her team found a set of 18 radiation-response genes, five of which were regulated by DNA sequence within or in neighboring the genes-so called cis regulators and 13 that were controlled by distant DNA sequences- trans regulators.
• As the researchers expected, a number of the regulatory sequence proved to be transcription factors, which bind to genes and turn their activity up or down. But to their surprise, the majority turned out not to be transcription factors. "And yet they still influence gene expression, so we are now trying to find out how they regulate gene expression levels," says Cheung.