Effects of nucleases on cell-free extrachromosomal circular DNA

Effects of nucleases on cell-free extrachromosomal circular DNA

Cell-free extrachromosomal circular DNA (eccDNA) as a distinct topological form from linear DNA has recently gained increasing research interest, with possible clinical applications as a class of biomarkers. In this study, we aimed to explore the relationship between nucleases and eccDNA characteris...

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Bibliographic Details
Published in:JCI insight Vol. 7; no. 8
Main Authors: Sin, Sarah Tk, Deng, Jiaen, Ji, Lu, Yukawa, Masashi, Chan, Rebecca Wy, Volpi, Stefano, Vaglio, Augusto, Fenaroli, Paride, Bocca, Paola, Cheng, Suk Hang, Wong, Danny Kl, Lui, Kathy O, Jiang, Peiyong, Chan, K C Allen, Chiu, Rossa Wk, Lo, Y M Dennis
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 22-04-2022
American Society for Clinical investigation
Subjects:
Animals
Deoxyribonucleases - genetics
DNA
DNA, Circular - genetics
Endodeoxyribonucleases - genetics
Endodeoxyribonucleases - metabolism
Female
Fetus - metabolism
Genetics
Humans
Mice
Mice, Knockout
Pregnancy
Genetics
Molecular diagnosis
Genetic diseases
Mouse models
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Summary:Cell-free extrachromosomal circular DNA (eccDNA) as a distinct topological form from linear DNA has recently gained increasing research interest, with possible clinical applications as a class of biomarkers. In this study, we aimed to explore the relationship between nucleases and eccDNA characteristics in plasma. By using knockout mouse models with deficiencies in deoxyribonuclease 1 (DNASE1) or deoxyribonuclease 1 like 3 (DNASE1L3), we found that cell-free eccDNA in Dnase1l3-/- mice exhibited larger size distributions than that in wild-type mice. Such size alterations were not found in tissue eccDNA of either Dnase1-/- or Dnase1l3-/- mice, suggesting that DNASE1L3 could digest eccDNA extracellularly but did not seem to affect intracellular eccDNA. Using a mouse pregnancy model, we observed that in Dnase1l3-/- mice pregnant with Dnase1l3+/- fetuses, the eccDNA in the maternal plasma was shorter compared with that of Dnase1l3-/- mice carrying Dnase1l3-/- fetuses, highlighting the systemic effects of circulating fetal DNASE1L3 degrading the maternal eccDNA extracellularly. Furthermore, plasma eccDNA in patients with DNASE1L3 mutations also exhibited longer size distributions than that in healthy controls. Taken together, this study provided a hitherto missing link between nuclease activity and the biological manifestations of eccDNA in plasma, paving the way for future biomarker development of this special form of DNA molecules.
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Authorship note: STKS, JD, and LJ are co–first authors.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.156070