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Proc Natl Acad Sci U S A. 2019 Jan 8;116(2):641-649. doi: 10.1073/pnas.1815031116. Epub 2018 Dec 28.

Dnase1l3 deletion causes aberrations in length and end-motif frequencies in plasma DNA.

Author information

1
Department of Pathology, New York University School of Medicine, New York, NY 10016.
2
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
3
Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China.
4
UMR 5164 Immunologie Conceptuelle, Expérimentale et Translationnelle, ImmunoConcEpT, Université de Bordeaux, 33076 Bordeaux, France.
5
Department of Pathology, New York University School of Medicine, New York, NY 10016; Boris.Reizis@nyulangone.org loym@cuhk.edu.hk.
6
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China; Boris.Reizis@nyulangone.org loym@cuhk.edu.hk.

Abstract

Circulating DNA in plasma consists of short DNA fragments. The biological processes generating such fragments are not well understood. DNASE1L3 is a secreted DNASE1-like nuclease capable of digesting DNA in chromatin, and its absence causes anti-DNA responses and autoimmunity in humans and mice. We found that the deletion of Dnase1l3 in mice resulted in aberrations in the fragmentation of plasma DNA. Such aberrations included an increase in short DNA molecules below 120 bp, which was positively correlated with anti-DNA antibody levels. We also observed an increase in long, multinucleosomal DNA molecules and decreased frequencies of the most common end motifs found in plasma DNA. These aberrations were independent of anti-DNA response, suggesting that they represented a primary effect of DNASE1L3 loss. Pregnant Dnase1l3 -/- mice carrying Dnase1l3 +/- fetuses showed a partial restoration of normal frequencies of plasma DNA end motifs, suggesting that DNASE1L3 from Dnase1l3-proficient fetuses could enter maternal systemic circulation and affect both fetal and maternal DNA fragmentation in a systemic as well as local manner. However, the observed shortening of circulating fetal DNA relative to maternal DNA was not affected by the deletion of Dnase1l3 Collectively, our findings demonstrate that DNASE1L3 plays a role in circulating plasma DNA homeostasis by enhancing fragmentation and influencing end-motif frequencies. These results support a distinct role of DNASE1L3 as a regulator of the physical form and availability of cell-free DNA and may have important implications for the mechanism whereby this enzyme prevents autoimmunity.

KEYWORDS:

cell-free DNA; cfDNA; liquid biopsy; noninvasive prenatal testing; systemic lupus erythematosus

PMID:
30593563
PMCID:
PMC6329986
DOI:
10.1073/pnas.1815031116
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: Y.M.D.L. is a scientific cofounder and a member of the scientific advisory board for Grail. Y.M.D.L., R.W.K.C., and K.C.A.C. hold equity in Grail and receive research funding from Grail/Cirina for other projects. Y.M.D.L., R.W.K.C., K.C.A.C., and P.J. are consultants to Grail. Y.M.D.L., R.W.K.C., and K.C.A.C. are cofounders and board members of DRA Company Limited. Y.M.D.L., R.W.Y.C., R.W.K.C., K.C.A.C., P.J., L.S., and B.R. plan to file a patent application based on the data generated from this work.

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