{"database":"biostudies-literature","file_versions":[],"scores":{"citationCount":0,"reanalysisCount":0,"viewCount":45,"searchCount":0},"additional":{"submitter":["Lan YY"],"funding":["NIDDK NIH HHS","NIAID NIH HHS","NIH HHS"],"pagination":["180-192"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4555847"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["9(1)"],"pubmed_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."],"journal":["Cell reports"],"pubmed_title":["Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy."],"pmcid":["PMC4555847"],"funding_grant_id":["T32 DK007540","DP2 OD002230","T32 DK007540-22","P30 DK057521","DK57521","P30 DK043351","T32 AI060548-05","T32 AI060548-04","DK43351","T32 AI060548"],"pubmed_authors":["Bouley R","Hacohen N","Rooney MS","Lan YY","Londono D"],"view_count":["45"],"additional_accession":[]},"is_claimable":false,"name":"Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy.","description":"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.","dates":{"release":"2014-01-01T00:00:00Z","publication":"2014 Oct","modification":"2024-11-20T21:37:19.401Z","creation":"2019-03-27T01:57:36Z"},"accession":"S-EPMC4555847","cross_references":{"pubmed":["25284779"],"doi":["10.1016/j.celrep.2014.08.074"]}}