Biology:DNASE1L1

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[3]

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.[4][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.[8]

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).[12][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.[11][17] In case of an abnormal result, clarification by imaging techniques is recommended.[16]

References

  1. ↑ "A muscle-specific DNase I-like gene in human Xq28". Human Molecular Genetics 4 (9): 1557–1564. September 1995. doi:10.1093/hmg/4.9.1557. PMID 8541839. 
  2. ↑ "Cloning of a gene encoding a DNase I-like endonuclease in the human Xq28 region". Gene 168 (2): 267–270. February 1996. doi:10.1016/0378-1119(95)00741-5. PMID 8654957. 
  3. ↑ 3.0 3.1 "DNASE1L1 deoxyribonuclease I-like 1". Entrez Gene. U.S. National Library of Medicine. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1774. 
  4. ↑ 4.0 4.1 "Isolation, differential splicing and protein expression of a DNase on the human X chromosome". Cell Death and Differentiation 3 (2): 199–206. April 1996. PMID 17180083. 
  5. ↑ , Hanswalter; Annemarie Poustka & Johannes Coy et al."Protein mit dnase-aktivität" patent EP0842278B1, issued 2005-11-09
  6. ↑ "Trashing the genome: the role of nucleases during apoptosis". Nature Reviews. Molecular Cell Biology 6 (9): 677–688. September 2005. doi:10.1038/nrm1715. PMID 16103871. 
  7. ↑ "Involvement of DNase gamma in apoptosis associated with myogenic differentiation of C2C12 cells". The Journal of Biological Chemistry 277 (34): 31031–31037. August 2002. doi:10.1074/jbc.M204038200. PMID 12050166. 
  8. ↑ 8.0 8.1 "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. PMID 19035302. 
  9. ↑ "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. doi:10.1016/s0090-8258(03)00061-1. PMID 12798698. 
  10. ↑ "A biomarker based detection and characterization of carcinomas exploiting two fundamental biophysical mechanisms in mammalian cells". BMC Cancer 13. December 2013. doi:10.1186/1471-2407-13-569. PMID 24304513. 
  11. ↑ 11.0 11.1 "Epitope Detection in Monocytes (EDIM) As a New Method of Liquid Biopsy in Pediatric Rhabdomyosarcoma". Biomedicines 10 (8): 1812. July 2022. doi:10.3390/biomedicines10081812. PMID 36009359. 
  12. ↑ 12.0 12.1 "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. doi:10.1016/j.oooo.2015.10.024. PMID 26747736. 
  13. ↑ "O583 Apol0 - A New Biomarker for Early Detection of Disorders of Cell Proliferation and Solid Tumours" (in en). International Journal of Gynecology & Obstetrics 119: S466–S467. October 2012. doi:10.1016/S0020-7292(12)61013-3. 
  14. ↑ "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. doi:10.3233/CBM-190414. PMID 31771043. 
  15. ↑ "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. doi:10.1093/carcin/bgm076. PMID 17420169. 
  16. ↑ 16.0 16.1 "Blood-Test Based Targeted Visualization Enables Early Detection of Premalignant and Malignant Tumors in Asymptomatic Individuals". Journal of Clinical and Medical Images 6 (9): 1–2. 2022-05-20. https://www.clinandmedimages.com/wp-content/uploads/2022/05/JCMI-v6-1541-1.pdf. Retrieved 2023-01-16. 
  17. ↑ "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. doi:10.1038/s41416-022-01855-x. PMID 35864157. 

Further reading



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