The report is published in the October 15th issue of Genes & Development.
Apoptosis, or programmed cell death, is a critical biological process in which superfluous or potentially harmful cells undergo a series of genetic changes that ultimately result in the death of the cell, and its engulfment by a neighboring cell. Apoptosis is involved in a number of developmental and pathological processes, including embryonic digit sculpting and cancer prevention. The morphological changes that characterize apoptosis include nuclear DNA fragmentation and digestion– although research has shown that cells can undergo apoptosis without DNA degradation.
Dr. Shigekazu Nagata and colleagues at Osaka University in Japan set out to determine the biological significance of apoptotic DNA degradation.
Dr. Nagata's group used Drosophila as a model organism because apoptosis has been largely conserved throughout evolution from flies to mammals. Both fly and mammalian cells contain several DNase enzymes that specifically degrade DNA. During apoptosis, a DNase called CAD is released from its inhibitor, ICAD, and thereby activated to chop up DNA inside the dying cell. The engulfing cell also houses DNases, including DNase II enzymes inside the lysosome (a specialized cellular compartment where ingested material is digested) that are thought to play a role in apoptotic DNA degradation.
Dr. Nagata and colleagues generated strains of flies deficient in ICAD, DNase II, or both ICAD and DNase II in order to determine the relative contributions of each of these enzymes to apoptotic DNA degradation, and the physiological consequences of this process. The researchers found that ICAD-deficient flies also do not express CAD (ICAD is required for the normal folding of the CAD protein, and therefore its activity) and so no apoptotic DNA fragmentation occurred. The DNase II-deficient flies were able to fragment DNA inside the dying cells, but the fragmented DNA accumulated and activated an innate immune response. Finally, flies deficient in both ICAD and DNase II lacked apoptotic DNA degradation abilities and had an enhanced immune response, compared to the flies solely deficient in DNase II.
These findings lend important mechanistic insight into the process of apoptotic DNA disposal: They demonstrate that CAD is the primary DNase responsible for DNA fragmentation in dying cells, and that it functions in a separate pathway from DNase II. But the study is considered to be particularly interesting because the experimental results point to a previously unrecognized role for innate immunity in apoptotic DNA degradation.
"In mammals or humans, the activation of innate immunity causes the expression of various cytokines [cell signaling molecules]…that can induce inflammation or septic shock. If our results in Drosophila can be applied to mammalian systems, they suggest that DNA of the dying cells must be properly deposited. Otherwise, we will suffer from an immune response, like septic shock," explains Dr. Nagata. Further research is needed to determine if undigested apoptotic DNA can elicit an immune response in humans, but if so, this finding could open up a whole new list of possible culprits behind human autoimmune disease.
Journal
Genes & Development