Dnase2a Deficiency Uncovers Lysosomal Clearance of Damaged Nuclear DNA via Autophagy
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Author(s)
Lan, Yuk Yuen
Bouley, Richard
Rooney, Michael S.
Hacohen, Nir
Londono, Diana
Rooney, Michael S.
Date Issued
October 2014
Journal
Cell Reports
Publisher
Elsevier
Citation
Lan, Yuk Yuen, Diana Londono, Richard Bouley, Michael S. Rooney, and Nir Hacohen. “Dnase2a Deficiency Uncovers Lysosomal Clearance of Damaged Nuclear DNA via Autophagy.” Cell Reports 9, no. 1 (October 2014): 180–92.
Version
Final published version
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[superscript −/−] 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.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
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DOI of Published Version
https://doi.org/10.1016/j.celrep.2014.08.074
