vival in response to exposure to ionizing irradiation, as occurs from such sources as the sun and X-rays.
However, they discovered that quiescent and proliferating blood stem cells initiate different types of DNA repair mechanisms once the cells have survived. Proliferating blood stem cells undergo DNA repair using a high-fidelity process known as homologous recombination, which has a minimal risk of acquiring mutations, as documented in the study.
Quiescent cells, on the other hand, use a mechanism known as nonhomologous end joining-mediated DNA repair, which often leads to misrepair of double strand breaks in the DNA. Such error prone repair can result in chromosomal deletions, insertions or translocations and subsequent genomic instability that can contribute to hematopoetic abnormalities. This, too, was documented in the study. The quiescent cells are limited to using the error prone NHEJ mechanism because of the constraint imposed by their cell cycle on the molecular composition of their DNA repair machinery.
"Our results demonstrate that quiescence is a double-edged sword, protecting hematopoetic stem cells from cellular stress but rendering them intrinsically vulnerable to mutagenesis following DNA damage," says senior author Emmanuelle Passegu, PhD, associate professor of medicine (division of hematology/oncology) and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.
The finding, the result of "heroic" research begun four years ago by Mary Mohrin, a graduate student in the Passegu lab, upturns current dogma, says Passegu. "The thinking has been that blood stem cells must proliferate to acquire the mutations that drive tumor development. This work says, 'not so.'"
While the repair mechanism used by the quiescent cells is defective, it is not detrimental for the body in evolutionary terms, says Passegu. "The blood stem cell system is designed to support the body
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| Contact: Jennifer O'Brien jobrien@pubaff.ucsf.edu 415-502-6397 University of California - San Francisco Source:Eurekalert |
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