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Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy

Yuk Yuen Lan1, Diana Londoño2, Richard Bouley3

  • 1Center 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.

Cell Reports
|October 7, 2014
PubMed

Insights

Deficiencies in DNA-degrading nucleases cause self DNA accumulation and autoimmunity. This study reveals a cellular process for removing damaged nuclear DNA via autophagy and lysosomes, preventing inflammation.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Biology

Background:

  • Deficiencies in DNA-degrading nucleases are linked to autoimmunity due to self DNA accumulation.
  • The precise sources of DNA and triggers for immunity remain incompletely understood.

Purpose of the Study:

  • To investigate the role of the lysosomal nuclease Dnase2a in DNA degradation and autoimmunity.
  • To elucidate the mechanisms of damaged nuclear DNA removal and its implications for cellular homeostasis.

Main Methods:

  • Analysis of mice deficient in Dnase2a.
  • Colocalization studies and live-cell imaging to track DNA.
  • Investigation of autophagy-mediated DNA delivery to lysosomes.
  • Assessment of inflammation via the Sting pathway.

Main Results:

  • Elevated undegraded DNA levels were observed in both phagocytic and nonphagocytic cells of Dnase2a-deficient mice.
  • Damaged nuclear DNA was identified as a major source of excess DNA in nonphagocytic cells.
  • Dnase2a-mediated DNA removal requires nuclear export and autophagy for lysosomal delivery.
  • Accumulated DNA in Dnase2a-deficient or autophagy-deficient cells induced inflammation through the Sting pathway.

Conclusions:

  • Dnase2a plays a crucial role in a cell-autonomous pathway for removing damaged nuclear DNA.
  • This pathway involves nuclear export, autophagy, and lysosomal degradation.
  • Dysregulation of this process can lead to DNA accumulation and inflammation, with implications for cancer and chemotherapy treatments.

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