DNASE1L1 explained

Deoxyribonuclease-1-like 1 is an enzyme that in humans is encoded by the DNASE1L1 gene.^{[1] [2] [3]} It is also known as DNaseX due to its localisation on the X chromosome.^[4]

This gene encodes a member of the deoxyribonuclease family and the protein and DNA shows high sequence similarity to lysosomal DNase I. Alternate transcriptional splice variants, encoding the same protein, have been characterized.

The DNase1L1/DNaseX gene was discovered in the early 1990s by Johannes F. Coy as a member of the Molecular Genome Analysis research project at the DKFZ (German Cancer Research Center) in Heidelberg and first published in 1996.^[5]

Just like the DNase I enzyme produced by the DNase I gene, the DNase1L1 (DNaseX) enzyme produced by the DNase1L1 (DNaseX) gene cuts double-stranded deoxyribonucleic acid (DNA) molecular chains into pieces. The cutting of DNA into 300-base pair pieces represents the final step in the execution of programmed cell death (apoptosis). Cells can then no longer perform cell division and thus cannot develop into tumor cells. DNase I and DNase1L1 (DNaseX) carry out programmed cell death (apoptosis) and thus protect the human body from the development of tumor cells. Conversely, the absence of DNase enzyme activity leads to the increased formation of tumor cells, as the execution of apoptosis is prevented.^{[6] [7]}

Importance

A fundamental common feature of all tumors is the disruption of apoptosis. Degenerated cells thus evade self-destruction, continue to grow and carry the risk of further degeneration through further mutations and increase in aggressiveness and malignancy.^[8]

DNaseX (DNase1L1) has a special feature that makes it suitable as a marker for the detection of cancer. The concentration of the DNaseX enzyme increases in tumor cells - in contrast to other DNases, whose concentration decreases in the course of tumor development.^[9]

DNaseX is generally produced in greater quantities in tumor cells in order to induce the desired programmed cell death. However, by synthesizing specific inhibitors, the tumor cell can suppress the enzyme activity of DNaseX and thus prevent the final apoptosis step, the DNA cutting.

The accumulation of DNaseX has been detected in all premalignant and malignant tumor types examined to date. The accumulation in cells occurs when DNaseX cannot fulfill its task. Then the cell continues to produce the DNaseX protein because it wants to induce apoptosis. This situation leads to higher and higher concentrations of DNaseX in the cell. If a DNaseX overproduction can be detected, this can be taken as an indicator of impaired apoptosis and as an indication of the development of tumors in the body.^{[10] [11] [12]}

The Apo10 epitope plays a special role in this process. This characteristic section of the protein sequence of the DNaseX enzyme can be identified diagnostically using the same-named monoclonal antibody Apo10 (DJ28D4).^{[13] [14] [15]}      

The resulting accumulation of DNaseX (Apo10) in the nucleus also makes the detection easier - since the amount of Apo10 in the nucleus increases sharply.    

Clinical application

DNaseX (Apo10) is already applied in diagnostic cancer screening. The enzymes DNaseX (Apo10) and TKTL1 are detected in PanTum Detect, a blood test used in combination with imaging techniques such as MRI and PET-CT for the early detection of cancer.^[16] The detection of DNaseX (Apo10) and TKTL1 in immune cells using EDIM technology provides clues to possible tumor disease.^[17] In case of an abnormal result, clarification by imaging techniques is recommended.

Further reading

• Chen EY, Zollo M, Mazzarella R, Ciccodicola A, Chen CN, Zuo L, Heiner C, Burough F, Repetto M, Schlessinger D, D'Urso M . 6 . Long-range sequence analysis in Xq28: thirteen known and six candidate genes in 219.4 kb of high GC DNA between the RCP/GCP and G6PD loci . Human Molecular Genetics . 5 . 5 . 659–668 . May 1996 . 8733135 . 10.1093/hmg/5.5.659 . vanc . free .
• Rodriguez AM, Rodin D, Nomura H, Morton CC, Weremowicz S, Schneider MC . Identification, localization, and expression of two novel human genes similar to deoxyribonuclease I . Genomics . 42 . 3 . 507–513 . June 1997 . 9205125 . 10.1006/geno.1997.4748 . vanc .
• Malferrari G, Mazza U, Tresoldi C, Rovida E, Nissim M, Mirabella M, Servidei S, Biunno I . 6 . Molecular characterization of a novel endonuclease (Xib) and possible involvement in lysosomal glycogen storage disorders . Experimental and Molecular Pathology . 66 . 2 . 123–130 . June 1999 . 10409440 . 10.1006/exmp.1999.2254 . vanc .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–1795 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW . 6 . Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation . Nature Biotechnology . 22 . 6 . 707–716 . June 2004 . 15146197 . 10.1038/nbt971 . vanc . 27764390 .
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A . 6 . From ORFeome to biology: a functional genomics pipeline . Genome Research . 14 . 10B . 2136–2144 . October 2004 . 15489336 . 528930 . 10.1101/gr.2576704 . vanc .
• Shiokawa D, Shika Y, Saito K, Yamazaki K, Tanuma S . Physical and biochemical properties of mammalian DNase X proteins: non-AUG translation initiation of porcine and bovine mRNAs for DNase X . The Biochemical Journal . 392 . Pt 3 . 511–517 . December 2005 . 16107205 . 1316290 . 10.1042/BJ20051114 . vanc .
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S . 6 . The LIFEdb database in 2006 . Nucleic Acids Research . 34 . Database issue . D415–D418 . January 2006 . 16381901 . 1347501 . 10.1093/nar/gkj139 . vanc .
• Coy JF, Velhagen I, Himmele R, Delius H, Poustka A, Zentgraf H . Isolation, differential splicing and protein expression of a DNase on the human X chromosome . Cell Death and Differentiation . 3 . 2 . 199–206 . April 1996 . 17180083 . vanc .

Notes and References

1. Parrish JE, Ciccodicola A, Wehhert M, Cox GF, Chen E, Nelson DL . A muscle-specific DNase I-like gene in human Xq28 . Human Molecular Genetics . 4 . 9 . 1557–1564 . September 1995 . 8541839 . 10.1093/hmg/4.9.1557 .
2. Pergolizzi R, Appierto V, Bosetti A, DeBellis GL, Rovida E, Biunno I . Cloning of a gene encoding a DNase I-like endonuclease in the human Xq28 region . Gene . 168 . 2 . 267–270 . February 1996 . 8654957 . 10.1016/0378-1119(95)00741-5 .
3. Web site: Entrez Gene . U.S. National Library of Medicine . DNASE1L1 deoxyribonuclease I-like 1.
4. Coy JF, Velhagen I, Himmele R, Delius H, Poustka A, Zentgraf H . Isolation, differential splicing and protein expression of a DNase on the human X chromosome . Cell Death and Differentiation . 3 . 2 . 199–206 . April 1996 . 17180083 .
5. EP0842278B1. Protein mit dnase-aktivität. 2005-11-09. Zentgraf. Poustka. Coy. Velhagen. Hanswalter. Annemarie. Johannes. Iris.
6. Samejima K, Earnshaw WC . Trashing the genome: the role of nucleases during apoptosis . Nature Reviews. Molecular Cell Biology . 6 . 9 . 677–688 . September 2005 . 16103871 . 10.1038/nrm1715 . 13948545 .
7. Shiokawa D, Kobayashi T, Tanuma S . Involvement of DNase gamma in apoptosis associated with myogenic differentiation of C2C12 cells . The Journal of Biological Chemistry . 277 . 34 . 31031–31037 . August 2002 . 12050166 . 10.1074/jbc.M204038200 . free .
8. Taper HS . Altered deoxyribonuclease activity in cancer cells and its role in non toxic adjuvant cancer therapy with mixed vitamins C and K3 . Anticancer Research . 28 . 5A . 2727–2732 . 2008 . 19035302 .
9. Zanotti S, Fisseler-Eckhoff A, Mannherz HG . Changes in the topological expression of markers of differentiation and apoptosis in defined stages of human cervical dysplasia and carcinoma . Gynecologic Oncology . 89 . 3 . 376–384 . June 2003 . 12798698 . 10.1016/s0090-8258(03)00061-1 .
10. Grimm M, Schmitt S, Teriete P, Biegner T, Stenzl A, Hennenlotter J, Muhs HJ, Munz A, Nadtotschi T, König K, Sänger J, Feyen O, Hofmann H, Reinert S, Coy JF . 6 . A biomarker based detection and characterization of carcinomas exploiting two fundamental biophysical mechanisms in mammalian cells . BMC Cancer . 13 . 569 . December 2013 . 24304513 . 4235042 . 10.1186/1471-2407-13-569 . free .
11. Urla C, Stagno MJ, Schmidt A, Handgretinger R, Fuchs J, Warmann SW, Schmid E . Epitope Detection in Monocytes (EDIM) As a New Method of Liquid Biopsy in Pediatric Rhabdomyosarcoma . Biomedicines . 10 . 8 . 1812 . July 2022 . 36009359 . 10.3390/biomedicines10081812 . 9404738 . free .
12. Grimm M, Feyen O, Coy JF, Hofmann H, Teriete P, Reinert S . Analysis of circulating CD14+/CD16+ monocyte-derived macrophages (MDMs) in the peripheral blood of patients with oral squamous cell carcinoma . Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology . 121 . 3 . 301–306 . March 2016 . 26747736 . 10.1016/j.oooo.2015.10.024 .
13. Rotmann AR, Hofmann HA, Coy JF . October 2012 . O583 Apol0 - A New Biomarker for Early Detection of Disorders of Cell Proliferation and Solid Tumours . International Journal of Gynecology & Obstetrics . en . 119 . S466–S467 . 10.1016/S0020-7292(12)61013-3. 76313286 .
14. Saman S, Stagno MJ, Warmann SW, Malek NP, Plentz RR, Schmid E . Biomarkers Apo10 and TKTL1: Epitope-detection in monocytes (EDIM) as a new diagnostic approach for cholangiocellular, pancreatic and colorectal carcinoma . Cancer Biomarkers . 27 . 1 . 129–137 . 2020 . 31771043 . 7029314 . 10.3233/CBM-190414 .
15. Lian F, Smith DE, Ernst H, Russell RM, Wang XD . Apo-10'-lycopenoic acid inhibits lung cancer cell growth in vitro, and suppresses lung tumorigenesis in the A/J mouse model in vivo . Carcinogenesis . 28 . 7 . 1567–1574 . July 2007 . 17420169 . 10.1093/carcin/bgm076 . free .
16. Burg S, Grust AL, Feyen O, Failing K, Banat GA, Coy JF, Grimm M, Gosau M, Smeets R . 6 . 2022-05-20 . Blood-Test Based Targeted Visualization Enables Early Detection of Premalignant and Malignant Tumors in Asymptomatic Individuals . 2023-01-16 . Journal of Clinical and Medical Images . 6 . 9 . 1–2 . 2023-03-26 . https://web.archive.org/web/20230326080928/http://clinandmedimages.com/wp-content/uploads/2022/05/JCMI-v6-1541-1.pdf . dead .
17. Stagno MJ, Schmidt A, Bochem J, Urla C, Handgretinger R, Cabanillas Stanchi KM, Saup R, Queudeville M, Fuchs J, Warmann SW, Schmid E . 6 . Epitope detection in monocytes (EDIM) for liquid biopsy including identification of GD2 in childhood neuroblastoma-a pilot study . British Journal of Cancer . 127 . 7 . 1324–1331 . October 2022 . 35864157 . 9519569 . 10.1038/s41416-022-01855-x .