Has DNA hydrolytic activity. Is capable of both single- and double-stranded DNA cleavage, producing DNA fragments with 3'-OH ends (By similarity). Can cleave chromatin to nucleosomal units and cleaves nucleosomal and liposome-coated DNA (PubMed:15796714, PubMed:19154352, PubMed:12095301). Acts in internucleosomal DNA fragmentation (INDF) during apoptosis and necrosis. The role in apoptosis includes myogenic and neuronal differentiation, and BCR-mediated clonal deletion of self-reactive B cells (PubMed:12050166, PubMed:15167901, PubMed:17218958, PubMed:24312463). Is active on chromatin in apoptotic cell-derived membrane-coated microparticles and thus suppresses anti-DNA autoimmunity (PubMed:15796714, PubMed:27293190). Together with DNASE1, plays a key role in degrading neutrophil extracellular traps (NETs) (PubMed:29191910). NETs are mainly composed of DNA fibers and are released by neutrophils to bind pathogens during inflammation (PubMed:29191910). Degradation of intravascular NETs by DNASE1 and DNASE1L3 is required to prevent formation of clots that obstruct blood vessels and cause organ damage following inflammation (PubMed:29191910). Inhibited by zinc. Inhibited by heparin and proteolysis by plasmin. Contradictory reports exist about the subcellular localization under normal physiological conditions. Shown to translocate to rough endoplasmic reticulum and to be transported through the entire secretory pathway for secretion. However, under conditions of cell death, may diffuse and/or be actively transported to the nucleus. Expressed at high levels in liver, spleen and testes. Expressed at lower levels in heart, lungs, skeletal muscle and kidney. Not expressed in brain. Predominantly expressed in macrophages; at protein level. Secreted by mononuclear phagocytes. Expression is first detected at embryonic day 11, and higher amounts were detected at days 15 and 17. Poly-ADP-ribosylated by PARP1. ADP-ribosylation negatively regulates enzymatic activity during apoptosis. Mice develop symptoms of the autoimmune disease systemic lupus erythematosus, characterized by high titers of anti-nuclear autoantibodies (ANA) directed against nucleosomes and double-stranded DNA, the deposition of immune complexes in glomeruli and full-blown glomerulonephritis (PubMed:27293190). Mice lacking both Dnase1 and Dnase1l3 show vascular occlusions following bacterial infection: defects are caused by the formation of intravascular neutrophil extracellular traps (NETs) clots that obstruct blood vessels and cause organ damage (PubMed:29191910). Belongs to the DNase I family.