By Riya Gandhi ‘22
Genotoxic stress is defined as an agent that disrupts or impairs genetic information within a cell and leads to mutations. If not repaired, these mutations often develop into cancer. Within epithelial stem cells, for example, there is a pathway called the DNA damage response (DDR) that halts the cell cycle and induces DNA repair or destruction of impaired cells through apoptosis. The effects of such genotoxic agents were the focus of researchers at the University of Freiburg in a recent study investigating methods of DDR regulation.
Under the direction of principal investigators Konrad Gronke and Pedro P. Hernández, scientists injected azoxymethane (AOM) into mice to trigger acute DNA damage; to document the production of interleukin-22 (IL-22), a regulator of the DDR machinery in intestinal epithelial stem cells, they injected the mice with additional doses of AOM. Four to five months after the initial AOM injection, tumor formation was analyzed; the researchers recorded that the mice’s rate of apoptosis had decreased while their tumor count had increased. Upon removal and analysis of the mice’s intestines, the scientists found that when mice were fed a glucosinolate-deficient diet — prior studies have shown metabolites of glucosinolates to be a source of genotoxic stress — they did not produce as much IL-22, which hindered the optimal functioning of the DDR. From this, the researchers deduced that successful initiation of the DDR requires IL-22; without IL-22 signals, carcinogens were more likely to lead to the transcription and translation of mutations, ultimately resulting in colon cancer.
This discovery is crucial to the medical field. By understanding how to regulate DDR, scientists may be able to create clinical therapies designed to maximize levels of protective factors such as IL-22 and thereby suppress chances of mutations and cancer.
- K. Gronke, et. al., Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature, (2019). doi: 10.1038/s41586-019-0899-7.
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