Deoxyribonuclease I Explained

Deoxyribonuclease I (usually called DNase I), is an endonuclease of the DNase family coded by the human gene DNASE1.^[1] DNase I is a nuclease that cleaves DNA preferentially at phosphodiester linkages adjacent to a pyrimidine nucleotide, yielding 5'-phosphate-terminated polynucleotides with a free hydroxyl group on position 3', on average producing tetranucleotides. It acts on single-stranded DNA, double-stranded DNA, and chromatin. In addition to its role as a waste-management endonuclease, it has been suggested to be one of the deoxyribonucleases responsible for DNA fragmentation during apoptosis.^[2]

DNase I binds to the cytoskeletal protein actin. It binds actin monomers with very high (sub-nanomolar) affinity and actin polymers with lower affinity. The function of this interaction is unclear. However, since actin-bound DNase I is enzymatically inactive, the DNase-actin complex might be a storage form of DNase I that prevents damage of the genetic information. This protein is stored in the zymogen granules of the nuclear envelope and functions by cleaving DNA in an endonucleolytic manner.

At least six autosomal codominant alleles of the gene DNASE 1 have been characterized, DNASE1*1 through DNASE1*6, and the sequence of DNASE1*2 represented in this record. Mutations in this gene, as well as factor inactivating its enzyme product, have been associated with systemic lupus erythematosus (SLE), an autoimmune disease.^{[3] [4]} A recombinant form of this protein is used to treat one of the symptoms of cystic fibrosis by hydrolyzing the extracellular DNA in sputum and reducing its viscosity.^[5] Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized.^[1]

In genomics

In genomics, DNase I hypersensitive sites are thought to be characterized by open, accessible chromatin; therefore, a DNase I sensitivity assay is a widely used methodology in genomics for identifying which regions of the genome are likely to contain active genes ^[6]

DNase I Sequence Specificity

It has been recently reported that DNase I shows some levels of sequence specificity that may depend on experimental conditions.^[7] In contrast to other enzymes which have high substrate specificity, DNase I certainly does not cleave with an absolute sequence specificity. However, cleavage at sites that contain C or G at their 3' end is less efficient.

Further reading

• Lachmann PJ . Lupus and desoxyribonuclease . Lupus . 12 . 3 . 202–6 . 2003 . 12708782 . 10.1191/0961203303lu357xx . 43058677 .
• Yasuda T, Awazu S, Sato W . Human genetically polymorphic deoxyribonuclease: purification, characterization, and multiplicity of urine deoxyribonuclease I . J. Biochem. . 108 . 3 . 393–8 . 1991 . 2277032 . 10.1093/oxfordjournals.jbchem.a123212. etal.
• Kishi K, Yasuda T, Ikehara Y . Human serum deoxyribonuclease I (DNase I) polymorphism: pattern similarities among isozymes from serum, urine, kidney, liver, and pancreas . Am. J. Hum. Genet. . 47 . 1 . 121–6 . 1990 . 2349940 . 1683738 . etal.
• Kabsch W, Mannherz HG, Suck D . Atomic structure of the actin:DNase I complex . Nature . 347 . 6288 . 37–44 . 1990 . 2395459 . 10.1038/347037a0 . 1990Natur.347...37K . 925337 . etal.
• Kishi K, Yasuda T, Awazu S, Mizuta K . Genetic polymorphism of human urine deoxyribonuclease I . Hum. Genet. . 81 . 3 . 295–7 . 1989 . 2921043 . 10.1007/BF00279009 . 20420713 .
• Rosenstreich DL, Tu JH, Kinkade PR . A human urine-derived interleukin 1 inhibitor. Homology with deoxyribonuclease I . J. Exp. Med. . 168 . 5 . 1767–79 . 1988 . 3263467 . 10.1084/jem.168.5.1767 . 2189114 . etal.
• Yasuda T, Nadano D, Takeshita H . Molecular analysis of the third allele of human deoxyribonuclease I polymorphism . Ann. Hum. Genet. . 59 . Pt 2 . 139–47 . 1995 . 7625762 . 10.1111/j.1469-1809.1995.tb00737.x . 43729378 . etal.
• Yasuda T, Kishi K, Yanagawa Y, Yoshida A . Structure of the human deoxyribonuclease I (DNase I) gene: identification of the nucleotide substitution that generates its classical genetic polymorphism . Ann. Hum. Genet. . 59 . Pt 1 . 1–15 . 1995 . 7762978 . 10.1111/j.1469-1809.1995.tb01601.x . 23914004 .
• Yasuda T, Nadano D, Iida R . Chromosomal assignment of the human deoxyribonuclease I gene, DNASE 1 (DNL1), to band 16p13.3 using the polymerase chain reaction . Cytogenet. Cell Genet. . 70 . 3–4 . 221–3 . 1995 . 7789176 . 10.1159/000134038 . etal.
• Yasuda T, Nadano D, Takeshita H . The molecular basis for genetic polymorphism of human deoxyribonuclease I: identification of the nucleotide substitution that generates the fourth allele . FEBS Lett. . 359 . 2–3 . 211–4 . 1995 . 7867802 . 10.1016/0014-5793(95)00037-A . 21461181 . etal.
• Yasuda T, Nadano D, Tenjo E . Genotyping of human deoxyribonuclease I polymorphism by the polymerase chain reaction . Electrophoresis . 16 . 10 . 1889–93 . 1996 . 8586059 . 10.1002/elps.11501601310 . 35528773 . etal.
• Iida R, Yasuda T, Takeshita H . Identification of the nucleotide substitution that generates the fourth polymorphic site in human deoxyribonuclease I (DNase I) . Hum. Genet. . 98 . 4 . 415–8 . 1996 . 8792814 . 10.1007/s004390050231 . 6393565 . etal.
• Iida R, Yasuda T, Aoyama M . The fifth allele of the human deoxyribonuclease I (DNase I) polymorphism . Electrophoresis . 18 . 11 . 1936–9 . 1998 . 9420147 . 10.1002/elps.1150181108 . 8969865 . etal.
• Yasuda T, Takeshita H, Iida R . A new allele, DNASE1*6, of human deoxyribonuclease I polymorphism encodes an Arg to Cys substitution responsible for its instability . Biochem. Biophys. Res. Commun. . 260 . 1 . 280–3 . 1999 . 10381379 . 10.1006/bbrc.1999.0900 . etal.
• Oliveri M, Daga A, Cantoni C . DNase I mediates internucleosomal DNA degradation in human cells undergoing drug-induced apoptosis . Eur. J. Immunol. . 31 . 3 . 743–51 . 2001 . 11241278 . 10.1002/1521-4141(200103)31:3<743::AID-IMMU743>3.0.CO;2-9 . 32330090 . etal.
• Otterbein LR, Graceffa P, Dominguez R . The crystal structure of uncomplexed actin in the ADP state . Science . 293 . 5530 . 708–11 . 2001 . 11474115 . 10.1126/science.1059700 . 12030018 .
• Yasutomo K, Horiuchi T, Kagami S . Mutation of DNASE1 in people with systemic lupus erythematosus . Nat. Genet. . 28 . 4 . 313–4 . 2001 . 11479590 . 10.1038/91070 . 21277651 . etal.
• Ballweber E, Galla M, Aktories K . Interaction of ADP-ribosylated actin with actin binding proteins . FEBS Lett. . 508 . 1 . 131–5 . 2001 . 11707283 . 10.1016/S0014-5793(01)03040-X . 7241702 . etal. free .
• Tsutsumi S, Kaneko Y, Asao T . DNase I is present in the chief cells of human and rat stomachs . Histochem. J. . 33 . 9–10 . 531–5 . 2002 . 12005024 . 10.1023/A:1014999624430 . 10324827 . etal.

Notes and References

1. Web site: Entrez Gene: DNASE1 deoxyribonuclease I.
2. Samejima, K. . Earnshaw, W.C. . amp . Trashing the genome: the role of nucleases during apoptosis . Nat Rev Mol Cell Biol . 6 . 677–88 . 2005 . 9 . 10.1038/nrm1715 . 16103871 . 13948545 .
3. Hakkim A, Fürnrohr BG, Amann K, Laube B, Abed UA, Brinkmann V, Herrmann M, Voll RE, Zychlinsky A . Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis . Proc Natl Acad Sci U S A. 107 . 21 . 9813–8 . 2010 . 20439745 . 10.1073/pnas.0909927107 . 2906830. 2010PNAS..107.9813H . free .
4. Yasutomo K, Horiuchi T, Kagami S . Mutation of DNASE1 in people with systemic lupus erythematosus . Nat. Genet. . 28 . 4 . 313–4 . 2001 . 11479590 . 10.1038/91070 . 21277651 . etal.
5. Shak S, Capon DJ, Hellmiss R . Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum . Proc. Natl. Acad. Sci. U.S.A. . 87 . 23 . 9188–92 . 1991 . 2251263 . 10.1073/pnas.87.23.9188 . 55129 . etal. free .
6. Boyle AP, Davis S, Shulha HP, Meltzer P, Margulies EH, Weng Z, Furey TS, Crawford GE . High-resolution mapping and characterization of open chromatin across the genome . Cell . 132 . 311–322 . 2008 . 2 . 10.1016/j.cell.2007.12.014 . 18243105 . 2669738.
7. Koohy. Hashem. Down, Thomas A. . Hubbard, Tim J. . Mariño-Ramírez, Leonardo . Chromatin Accessibility Data Sets Show Bias Due to Sequence Specificity of the DNase I Enzyme. PLOS ONE. 26 July 2013. 8. 7. e69853. 10.1371/journal.pone.0069853 . 23922824 . 3724795. 2013PLoSO...869853K. free.