Tina Thornton, Ph.D., UVM Research Associate in Medicine (left), and Mercedes Rincon, Ph.D., UVM Professor of Medicine. (Photo: COM Design & Photography)
Are we genetically doomed when the double helix we all identify with DNA breaks? No, say a team of researchers led by University of Vermont (UVM) immunologists, who discovered a novel mechanism that provides life support to cells while DNA double-strand break repairs are in progress.
The study, authored by Mercedes Rincon, Ph.D., UVM professor of medicine, and Tina Thornton, Ph.D., UVM research associate in medicine, was published recently in Nature Communications.
Rincon’s and Thornton’s findings reveal that a novel mechanism, which is selectively initiated in response to DNA breaks, is vital to ensuring that B cells in our immune system stay alive while they produce protective antibodies, which is a natural process that involves DNA breakage. This novel mechanism involves the modification of a molecule called GSK3β, a protein that normally causes cells to die.
“In response to DNA breakage, GSK3β is modified by so-called ‘phosphorylation’ at the 389-position in the molecule,” explains Thornton. “This modification causes the shutdown of GSK3β, and as a result, cells survive while repairing their DNA breaks.”
The study’s findings demonstrate that when this modification of GSK3β fails to occur due to a mutation of GSK3β at the 389-position, B cells of the immune system die while trying to repair the DNA breaks.
“These B cells die by an unusual type of death called necroptosis,” says Rincon. “B cells are the cells that produce the antibodies that protect us after vaccination, so when more of them die, fewer antibodies are produced and the immune system becomes weaker.” Indeed, the researchers found that when the 389-position in the GSK3β was mutated, almost no antibodies were detected after immunization.
“This is the first time that the GSK3β molecule has been connected to antibody production by the B cells in the immune system,” says Rincon, who adds that these finding could have a major impact on vaccine design and individual responses to infectious agents.
Rincon believes that the team’s findings could lead to a biomarker test to determine exposure to radiation, since radiation is a well-known cause of DNA breakage, and could be developed into a novel, highly-sensitive diagnostic/screening test.
Together with Ruth Heimann, M.D., UVM professor of radiology, the group has demonstrated the sensitivity of GSK3β phosphorylation detection as a marker for radiation exposure in cancer patients who have received radiotherapy.
“In addition, this type of test could be used to determine if deployed military personnel could have been exposed to depleted uranium radiation,” Rincon says.