More than tripling the number of mutant genes known to influence radiation damage, the work was carried out at the National Institute of Environmental Health Sciences and reported today in the journal Nature Genetics. Previously, fewer than 30 such genes were known.
"Most of the newly characterized mutant genes not only protect against gamma radiation but provide resistance to other damaging agents, such as ultraviolet light and the commonly used anti-cancer drugs bleomycin and camptothecin," the two senior authors Michael A. Resnick, Ph.D and Craig B. Bennett, Ph.D., said in a joint statement.
"So we anticipate," their statement continued, "that these findings will lead not only to new human genes that determine resistance to genetic damage - but to genes that drug manufacturers can target to make more effective anti-cancer drugs."
Like many other recent advances in genetic understanding, today's work was done using common bakers yeast, called Saccharomyces cerevisiae, the living substance that makes bread dough rise. This yeast has been a model system for much molecular genetic research for more than three decades because its basic cellular mechanisms also exist in mammals. The Resnick laboratory, where the work was performed, pioneered the use of yeast over 25 years ago in genetic and molecular studies to understand how DNA double-strand breaks, the major source of radiation-induced genetic damage and change, are produced and repaired by cells.
So many human and mammalian disease genes, as well as genes associated with the repair of ionizing radiation damage, have subsequently been first characterized in yeast that Dr. Resnick co-authored an only slightly tongue-in-cheek scientific report last year in Mutation Research called "Yeast as honorary mammal."
Sixty-nine of the 107 newly discovered yeast genes affecting responses to radiation are similar to genes in human. Seventeen of the 69 are similar to known human genes implicated in cancer.
"Our discovery," Dr. Bennett said, "demonstrates how really important many of these genes that are 'non-essential' may be, especially in regard to our susceptibility to the environment - radiation, cigarette smoke, solvents and other chemicals, drugs and even certain foods." Non-essential genes are those which an organism can literally live without - that is, the organism or body can still grow if the gene is damaged or even deleted. Some can become essential when an environmental stress like radiation comes along.
The new study was made possible when a consortium, the Yeast Genome Deletion Project, created sets of yeast strains with a different non-essential gene deleted from each. To make this huge amount of genetic material rapidly available to the research community, the strains were distributed by a private company. The NIEHS laboratory irradiated one sample of each strain and a second set was kept as a control. When an irradiated mutant strain failed to thrive and grow, compared to the non-irradiated one, the deleted gene was considered to affect how the organism resisted radiation.
"The difference between our study and earlier studies was that we used diploid cells," Dr. Bennett said. "Human cells, except for sperm and unfertilized ova, are diploid - meaning each cell has two sets of every gene on two sets of chromosomes, one from the mother and one from the father. Yeast cells, however, vary. They can be either haploid - having a single set of genes - or diploid."
"We reasoned that organisms with two copies of chromosomes, like humans, might respond differently to radiation," Dr. Resnick said, "so we used diploid yeast - and, indeed, found many more genes influencing radiation responses." This approach may explain why several new classes of genes were found that deal with environmental insults.
Collaborating with Drs. Resnick and Bennett at the NIEHS laboratory were Kevin Lewis, Ph.D., now at Southwest Texas University, visiting researchers Gopalakrishnan Karthikeyan, Ph.D.,from India, Kirill S. Lobachev, Ph.D., from Russia, Yong H. Jin, Ph.D., from Korea, along with biologists Joan F. Sterling, and Joyce R. Snipe.
The 107 newly identified radiation-related genes, along with some 23 that were previously identified (and re-identified by the current method) bring the total to 130. These were revealed from the study of just two-thirds of the non-essential genes. The number of radiation-protective genes will likely grow to 170 or so, the researchers speculated, when the remaining 1,200 non-essential genes are examined by Dr. Bennett, now of the Duke University Medical Center in Durham, N.C., Dr. Resnick and their colleagues.
"We are in a very exciting transition to 'functional genomics,'" Dr. Resnick said. "Other new technologies can show whether a substance or environmental factor turns an individual gene 'on' or 'off,' and now we can begin to tell whether that switch means something important. The work in yeast should help illuminate what the gene does within the human body."
NIEHS Media Contacts:
Bill Grigg (301) 402-3378
Lou Rozier (919) 541-1993
Dr. Resnick may be reached at (919) 541-4480.
Dr. Bennett is at (919) 681-2902.