Disease relevance of DNASE1L3

• Ectopic expression of DNAS1L3 conferred on osteosarcoma cells the ability to undergo VP-16-induced internucleosomal DNA fragmentation [1].
• Our results suggest that DNAS1L3 plays an active role in lymphoma cell sensitization to VP-16 and that its deficiency may constitute a novel mechanism of drug resistance in these cells [2].
• The authors investigated whether gene transfer of this DNase-gamma exerts some therapeutic effects on human glioma cells [3].
• Involvement of DNase gamma in apoptotic DNA fragmentation in histiocytic necrotizing lymphadenitis [4].
• Moreover, the ratio of DNase gamma immunoreactivity to TUNEL reactivity, which represents probability of apoptosis relevant to DNase gamma, was higher in foci of nuclear debris in HNL than in the hyperplastic paracortex in lymphadenopathy including T-cell apoptosis [4].

High impact information on DNASE1L3

• The Poly(ADP-ribose) polymerase-1-regulated endonuclease DNAS1L3 is required for etoposide-induced internucleosomal DNA fragmentation and increases etoposide cytotoxicity in transfected osteosarcoma cells [1].
• Recently, we showed that these cells also do not express the poly(ADP-ribosyl)ation-regulated Ca(2+)- and Mg(2+)-dependent endonuclease DNAS1L3 [1].
• These results indicate that PARP-1 cleavage during apoptosis is not simply required to prevent excessive depletion of NAD and ATP but is also necessary to release DNAS1L3 from poly(ADP-ribosyl)ation-mediated inhibition [5].
• Regulation of DNAS1L3 endonuclease activity by poly(ADP-ribosyl)ation during etoposide-induced apoptosis. Role of poly(ADP-ribose) polymerase-1 cleavage in endonuclease activation [5].
• The DNAS1L3 protein also underwent poly(ADP-ribosyl)ation in transfected mouse skin fibroblasts in response to inducers of apoptosis [6].

Biological context of DNASE1L3

• DNAS1L2 is located on a 16p13.3 cosmid, while DNAS1L3 maps to 3p14.3-p21.1 by fluorescence in situ hybridization and by PCR analysis of a radiation hybrid panel [7].
• In contrast, medium conditioned by the macrophage enzyme DNASE1-like 3 (DNASE1L3 or D3) erects a potent in vitro barrier to liposomal transfection [8].
• Characterization of human DNase I family endonucleases and activation of DNase gamma during apoptosis [9].
• We report here on the nucleotide sequence of the cDNA encoding human DNase gamma, which is a candidate for an apoptotic endonuclease [10].
• The cDNA clone isolated from a human spleen cDNA library is composed of a 918 bp open reading frame encoding a 305 amino acid precursor protein for DNase gamma [10].

Anatomical context of DNASE1L3

• Overexpression of DNase gamma in the mutation-competent Ramos B-cell line resulted in a marked increase in the resected but not blunt DSBs in the V region [11].
• An enhancement of caspase-3 activity and collapse of mitochondrial membrane potential underlie DNAS1L3-mediated sensitization of Daudi cells to VP-16, which may be a direct result of DNAS1L3-mediated increase in PARP-1-activating DNA breaks after VP-16 treatment [2].
• DNAS1L3 expression potentiated the cytotoxic effect of acetaminophen in HeLa cells suggesting an active role in the death process induced by this drug [12].
• Presence of DNase gamma-like endonuclease in nuclei of neuronal differentiated PC12 cells [13].

Associations of DNASE1L3 with chemical compounds

• These results suggested that O2- was responsible for TBR-induced apoptosis, and Ca(2+)-dependent and caspase-3-independent nuclease such as DNase gamma played an important role in apoptotic signaling triggered by Golgi dysfunction [14].
• [Ca2+]i-chelating BAPTA-AM (5 microM) and/or DNase gamma-inhibiting Zn2+ (0.5 mM) inhibited approximately 50% of induced apoptosis and DNA-laddering, indicating a 50% participation of Ca2+/Mg2+-dependent DNase gamma [15].
• Fluorescein and triazine derivatives, partial structures of DR396, had little inhibitory activity for DNase gamma [16].

Regulatory relationships of DNASE1L3

• Collectively, these findings indicate that IFN-beta induced apoptosis in human glioma cells through activation of caspase-7 and activation of DNase-gamma [17].

Other interactions of DNASE1L3

• Northern analysis revealed DNAS1L3 expression nearly exclusively in liver, while DNAS1L2 expression was detected in brain by RT-PCR [7].
• A comparison of DNAS1L1, DNAS1L2, and DNAS1L3 with the well-characterized DNase I suggests that the DNAS1L proteins are unlikely to be glycosylated or bind actin; however, catalytic and calcium- and DNA-binding residues are conserved, and potentially cleavable signal peptides are present among all these proteins [7].
• Characterization of thioredoxin-DNase gamma fusion protein (Trx-hDNase gamma) shows that the recombinant protein has a Ca(2+)/Mg(2+)- or Mn(2+)-dependent endonuclease activity that cleaves chromatin DNA to nucleosomal units [10].
• Here we show that DNase gamma, a member of DNase I family of endonucleases, is expressed in GC B cells and CD40-stimulated B cells [11].
• Induction of apoptosis was related to the level of intracellular mRNA of interferon-beta, prolongation of the phosphorylation time of molecules in the interferon-beta signal transduction pathway, such as JAK1, Trk2, and STAT1, and activation of DNase gamma [18].

Analytical, diagnostic and therapeutic context of DNASE1L3

• Northern blot analysis reveals that the expression of a single transcript of 1.5 kb DNase gamma mRNA is detected in the spleen and liver [10].
• Sequence analysis reveals that LS-DNase shares 46% amino acid sequence identity with DNase I [19].
• The specific detection of DNase gamma in apoptotic nuclei is confirmed by indirect-immunofluorescence analysis using TNF-alpha-induced apoptotic HeLa S3 cells transfected with DNase gamma [20].
• In Western blot analysis, hg303 recognizes both wild type and C-terminal Myc-His-tagged human DNase gamma, but does not cross-react with human DNase I family members, DNase I, DNase X, or DNAS1L2 [20].
• Immunoreactivity for DNase gamma was detected in fragmented and condensed nuclei found abundantly in HNL as well as TUNEL reactivity [4].

References