The Nexus of cfDNA and Nuclease Biology

Abstract

Cell-free DNA (cfDNA) is a widely used noninvasive biomarker for diagnosis and prognosis of multiple disease states. Emerging evidence suggests that cfDNA might not just be passive waste products of cell death but could have a physiological and pathological function in inflammation and autoimmunity. The balance of cfDNA generation and clearance may thus be vital in health and disease. In particular, plasma nuclease activity has been linked to multiple pathologies including cancer and systemic lupus erythematosus (SLE) and associated with profound changes in the nonrandom fragmentation of cfDNA. Lastly, in this review, we explore the effects of DNA fragmentation factor B (DFFB), DNASE1L3, and DNASE1 on cfDNA levels and their fragmentomic profiles, and what these recent insights reveal about the biology of cfDNA. HighlightsCell-free DNA (cfDNA) is unlikely to be inert and may have a pathophysiological role in inflammation and autoimmune conditions like systemic lupus erythematosus (SLE).Nucleases are involved in both cfDNA generation and clearance; specifically cfDNA generation involves DFFB and DNASE1L3, while cfDNA clearance involves DNASE1L3 and DNASE1.

Dimethylamino group modified polydopamine nanoparticles with positive charges to scavenge cell-free DNA for rheumatoid arthritis therapy

“…Increasing evidences suggested that cfDNA played an active role in inflammatory diseases. It also tightly participated in immune responses in physiological conditions and lead to sterile inflammation in pathological conditions [ 2 , 3 ]. Specifically, in rheumatoid arthritis (RA) patients, the levels of cfDNA in synovial fluid (SF) and peripheral blood were highly elevated [ 4 ].…”

Role of Cell-Free DNA and Deoxyribonucleases in Tumor Progression

“…Therefore, DNase IL3 can degrade chromatin-associated DNA more efficiently than DNase I, which preferably 'eats' naked DNA [145]; DNase I is more efficient in cleaving naked DNA [144]. Apparently, DNase IL3 is not inactivated by actin in the cytoplasm or in the blood [117]. The data obtained indicate that DNase IL3 should be recruited actively during apoptotic and inflammatory processes at relatively early stages, before DNase I.…”

“…The half-life of cfDNA is quite short, estimated to be between 16 min and 2 h [116]. There are at least three potential mechanisms of DNA excretion from the blood: active uptake by the reticuloendothelial system in the liver and spleen, passive filtration by the renal system and direct degradation by nucleases [117].…”

“…In blood there are generous amounts of enzymes capable of destroying cfDNA including DNase I and DNase IL3, and also more rare nucleases such as EndoG, apoptosis-inducing factor (AIF), topoisomerase II and cyclophilins [138]. Two circulating DNases, DNase I and DNase IL3, have been shown to have a significant effect on cfDNA levels and/or the enrichment of certain cfDNA fragments [117]. The main role of circulating DNases in an organism is the digestion of the DNA received with food in the intestinal tract.…”

“…Decoding the role of nucleases in the regulation of the level/enrichment of cfDNA is difficult due to the presence of various nucleases in the human body and the ability of nucleases to act both in generating cfDNA through cell death pathways such as apoptosis and in the clearance of cfDNA at the blood level. A deficiency of a particular nuclease can be masked by the action of other nucleases [117]. Changes in the activity of DNases in the early (A) and late (B) stages of tumorigenesis.…”