Disease relevance of DNASE1

• The patients with severe RSTS all had deletions comprising telomeric neighbor genes of CREBBP, including DNASE1, a dominant gene encoding a nuclease that has been associated with systemic lupus erythematodes [1].
• Background: The single nucleotide polymorphism (SNP) at deoxyribonuclease I (DNase I), designated as DNASE1 (NCBI SNP number; 1053874), in exon 8 (A2317G) is considered to be one of the susceptibility genes for gastric and colorectal carcinoma and myocardial infarction [2].
• We first mapped the transcription start sites of DNASE1 in human pancreas and in the DNase I-producing human pancreatic cancer cell line QGP-1, and revealed a novel site approximately 12 kb upstream of exon 1, which was previously believed to be the single transcription-starting exon [3].
• A history of gastrointestinal complications attributed to cystic fibrosis and the use of histamine H2-receptor blockers, corticosteroids, or recombinant human DNase (dornase alfa) were associated with a higher incidence of fibrosing colonopathy [4].
• The overall contribution of individual DNase-I hypersensitive sites to the expression of the gene was then studied using a series of mutants that were stably transfected into mouse erythroleukemia cells [5].

High impact information on DNASE1

• Mutation of DNASE1 in people with systemic lupus erythematosus [6].
• Dornase-alfa for cystic fibrosis [7].
• A biochemical assay employing DNase-I affinity chromatography, two-dimensional peptide analysis and SDS polyacrylamide gel electrophoresis was used to isolate, identify, and assess the amount of actin from gonial cells of the crane fly, Nephrotoma suturalis [8].
• DNase-I-dependent dissociation of erythrocyte cytoskeletons [9].
• Distinct DNase-I hypersensitive sites are associated with TAL-1 transcription in erythroid and T-cell lines [10].

Chemical compound and disease context of DNASE1

• DNase I hypersensitivity and chromatin immunoprecipitation assays using u-PAR-expressing colon cancer cells indicated a hypersensitive region (+665/+2068) in intron 1 enriched with acetylated histone 3 (H3) and H3 methylated at lysine 4, markers of regulatory regions [11].
• Treatment of rat hepatoma cells with insulin, glucagon, thyroxine (T4) and triiodothyronine (T3) caused a concentration-dependent decrease in the monomeric actin content as measured by the deoxyribonuclease-I inhibition assay [12].
• Furthermore, administration of probiotic DNA ameliorated the severity of experimental colitis, whereas methylated probiotic DNA, calf thymus DNA, and Dnase-treated probiotics had no effect [13].
• No cure exists for respiratory syncytial virus infection, but commonly employed palliative treatments include oxygen, inhaled beta(2) agonists, racemic epinephrine, dornase alfa, systemic and inhaled corticosteroids, inhaled ribavirin, and nasopharyngeal suctioning [14].

Biological context of DNASE1

• Family studies showed that the three common phenotypes - DNASE1 1, 1-2, and 2 - and the other four rare phenotypes - DNASE1 1-3, 2-3, 2-4, and 3-4 - represent homozygosity or heterozygosity for four autosomal codominant alleles, DNASE1*1, *2, *3, and *4 [15].
• To localize the human deoxyribonuclease I (DNase I) gene, DNASE1 (DNL1), we performed a polymerase chain reaction (PCR) using DNA extracted from a panel of cloned human x rodent hybrid cell lines carrying different human chromosomes and screened for the presence of the expected PCR products [16].
• Turks had the highest allele frequency for DNASE1 *2, HumDN1 *4, and HumDN1 *5 [2].
• Conclusions: This study is the first to demonstrate the simultaneous genotyping of DNASE1 and HumDN1 polymorphisms and reveal the existence of a certain genetic heterogeneity in the worldwide distribution of these two polymorphisms [2].
• These results suggest that human DNASE1 expression is regulated through the use of alternative promoter and alternative splicing [3].

Anatomical context of DNASE1

• Furthermore, RT-PCR analysis indicated alternative splicing of human DNASE1 pre-mRNA in pancreas and QGP-1 cells [3].
• Dornase alfa has been found to increase the pourability and reduce the viscoelasticity of CF sputum in vitro and, in an animal model, to increase its mucociliary transportability [17].
• The illegitimate apo A-II transcriptional activity observed in Caco-2 cells is linked to the presence of DNase-I hypersensitive sites within the enhancer [18].
• DNase-I hypersensitive sites were detected within 1 kbp upstream of exon I in chromatin structures of type II pneumocyte cell line A549 and utero-cervical cell line HeLa, both of which express SLPI mRNA transcripts [19].
• Whole egg mounts, egg fragments, cryosections, and cortical membrane patches probed with rhodamine phalloidin, fluorescent DNase-I, or anti-actin antibody showed the cortical cytoskeleton to contain two domains of actin: filamentous and nonfilamentous [20].

Associations of DNASE1 with chemical compounds

• Persistence of the ten-nucleotide repeat in chromatin unfolded in urea, as revealed by digestion with deoxyribonuclease i [21].
• A large-scale, long-term, Phase III clinical trial, consisting of a 24-week double-blind period and a 24-week open-label extension, confirmed these findings and further demonstrated that dornase alfa reduces the incidence of respiratory tract infectious exacerbations requiring parenteral antibiotic therapy [17].
• Chromatin bound thyroid hormone receptor and v-erbA generate Dnase I hypersensitive sites independent of ligand [22].
• The 52-kilodalton Dnase was purified in the active form to near homogeneity by ammonium sulfate precipitation and successive chromatographies on phosphocellulose, DNA-cellulose, and gel filtration columns [23].
• Sites of preferential DNase-I nicking were made visible by the incorporation of biotin-labeled dUTP and subsequent binding of the streptavidin-peroxidase complex [24].

Regulatory relationships of DNASE1

• For example, the differentially methylated 5 -portion of the human SNRPN gene-a sequence element that controls imprinting in the Prader-Willi and Angelman syndromes' domain on chromosome 15q11- q13-has strong DNase-I hypersensitive sites on the unmethylated paternal chromosome (4) [25].

Other interactions of DNASE1

• Total RNA was treated with 0.5 units of Rnase-free Dnase/mg of RNA to remove any contaminating DNA [26].
• Chromosomal assignment of the human deoxyribonuclease I gene, DNASE 1 (DNL1), to band 16p13.3 using the polymerase chain reaction [16].
• The function of the SLPI promoter encompassing these DNase-I hypersensitive sites has been studied by deletion analysis with the luciferase gene as a transient expression vector [19].
• Characterization of DNASE I hypersensitive sites in the 120kb 5' to the CFTR gene [27].
• CONCLUSIONS: Pulmonary function as measured by FEV1 and FVC improved significantly in the dornase alfa-treated patients [28].

Analytical, diagnostic and therapeutic context of DNASE1

• Sequence analysis combined with gel retardation and Dnase 1 footprinting assay identified multiple cis and trans elements for this fragment, including Sp1, PEA3, cyclic AMP response element (CRE)-like sequence, and E-boxes [29].
• Both mobility shift assay and DNase-I footprint analysis showed that P2 had much higher Pit-1 binding affinity than P1 [30].
• Dornase alfa also decreased the rate of hospitalizations, the number of days missed from work or school, and the frequency of CF-related symptoms [17].
• Short-term (10-day) Phase I and II clinical trials showed dornase alfa to be safe and effective in improving pulmonary function in clinically stable CF patients with mild to moderate pulmonary disease (FVC > or = 40% of predicted value) [17].
• The control group consisted of 2382 patients who had never received dornase alfa [31].

References