title: Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy.
abstract: Deficiencies in DNA-degrading nucleases lead to accumulation of self DNA and induction of autoimmunity in mice and in monogenic and polygenic human diseases. However, the sources of DNA and the mechanisms that trigger immunity remain unclear. We analyzed mice deficient for the lysosomal nuclease Dnase2a and observed elevated levels of undegraded DNA in both phagocytic and nonphagocytic cells. In nonphagocytic cells, the excess DNA originated from damaged DNA in the nucleus based on colocalization studies, live-cell imaging, and exacerbation by DNA-damaging agents. Removal of damaged DNA by Dnase2a required nuclear export and autophagy-mediated delivery of the DNA to lysosomes. Finally, DNA was found to accumulate in Dnase2a(-/-) or autophagy-deficient cells and induce inflammation via the Sting cytosolic DNA-sensing pathway. Our results reveal a cell-autonomous process for removal of damaged nuclear DNA with implications for conditions with elevated DNA damage, such as inflammation, cancer, and chemotherapy.
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, 149 13(th) Street, Charlestown, MA 02129, USA; Broad Institute, 415 Main Street, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Yuk Yuen
authors.initials: YY
authors.lastname: Lan
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, 149 13(th) Street, Charlestown, MA 02129, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Londoño
authors.affiliation: Center for Systems Biology, Program in Membrane Biology and Nephrology Division, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bouley
authors.affiliation: Broad Institute, 415 Main Street, Cambridge, MA 02142, USA; Harvard/MIT Division of Health Sciences and Technology, Cambridge, MA 02139, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Rooney
authors.affiliation: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, 149 13(th) Street, Charlestown, MA 02129, USA; Broad Institute, 415 Main Street, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Electronic address: nhacohen@partners.org.
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage; D004706:Endodeoxyribonucleases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D010586:Phagocytes / Q000166:cytology / Q000201:enzymology
chemical_list: D004247:DNA; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II