DNase γ, DNase I and caspase‐activated DNase cooperate to degrade dead cells

Abstract

Serum endonucleases are essential for degrading the chromatin released from dead cells and preventing autoimmune diseases such as systemic lupus erythematosus. Serum DNase I is known as the major endonuclease, but recently, another endonuclease, DNase c/DNase I-like 3, gained attention. However, the precise role of each endonuclease, especially that of DNase c, remains unclear. In this study, we distinguished the activities of DNase c from those of DNase I in mouse serum and concluded that both cooperated in degrading DNA during necrosis: DNase c functions as the primary chromatolytic activity, causing internucleosomal DNA fragmentation, and DNase I as the secondary one, causing random DNA digestion for its complete degradation. These results were confirmed by two in vivo experimental mouse models, in which necrosis was induced, acetaminophen-induced hepatic injury and streptozotocin-induced b-cell necrosis models. We also determined that DNase c functions as a backup endonuclease for caspase-activated DNase (CAD) in the secondary necrosis phase after c-ray-induced apoptosis in vivo.

Human CD8+ T Cells Release Extracellular Traps Co-Localized With Cytotoxic Vesicles That Are Associated With Lesion Progression and Severity in Human Leishmaniasis

“…Moreover, DNAse I treatment decreased DNA quantification in the supernatants from anti-CD3/anti-CD28-stimulated cultures, confirming that the DNA collected in the culture supernatant was double-stranded DNA, as previously shown in other models of etosis (14,48). Necrosis activates intracellular DNAse to cleave DNA, which explains the low quantification of DNA released in necrosis (49). The presence of LETs was detected using DAPI and PI, which is a DNA intercalating agent, used in other studies to show the presence of DNA in ETs (46).…”

The Biology of Cell-free DNA Fragmentation and the Roles of DNASE1, DNASE1L3, and DFFB

“…23,32 It has been suggested that, in its role as an apoptotic intracellular endonuclease, DNASE1L3 cooperates with DFFB in DNA fragmentation. 32,33 When we compared the fragment end profiles of newly released cf.DNA with that of Dna-se1l3-deficient mice, we found a noticeable attenuation of the periodicity in A-end fragments, and especially in the A< >C fragment. We suspect that this attenuation is due to the coexisting intracellular activity of DNASE1L3 during the generation of newly fragmented DNA from apoptosis in WT versus in Dnase1l3-deficient mice.…”

DNase γ-dependent DNA fragmentation causes karyolysis in necrotic hepatocyte

“…We studied an endonuclease, DNase γ (also known as DNase1L3), that is a secreting protein of the DNase I family and causes DNA fragmentation in necrosis [8]. Previously, we generated DNase γ gene deficient (DNase γ −/− ) mice and induced hepatocyte necrosis by acetaminophen (APAP) overdose [7]. We found that karyolysis was inhibited in the treated hepatocyte, suggesting that DNase γ was essential for the process.…”