Dsup

Dsup (contraction of damage suppressor) is a DNA-associating protein, unique to the tardigrade, that suppresses the occurrence of DNA breaks by radiation.[1][2][3][4] When human HEK293 cells were engineered with Dsup proteins, they showed approximately 40% more tolerance against X-ray radiation.[4]

Damage suppressor protein
Identifiers
OrganismRamazzottius varieornatus
SymbolDsup
UniProtP0DOW4
Search for
StructuresSwiss-model
DomainsInterPro

Tardigrades can withstand 1,000 times more radiation than other animals,[5] median lethal doses of 5,000 Gy (of gamma rays) and 6,200 Gy (of heavy ions) in hydrated animals (5 to 10 Gy could be fatal to a human).[6] The only explanation found in earlier experiments for this ability was that their lowered water state provides fewer reactants for ionizing radiation.[6] However, subsequent research found that tardigrades, when hydrated, still remain highly resistant to shortwave UV radiation in comparison to other animals, and that one factor for this is their ability to efficiently repair damage to their DNA resulting from that exposure.[7] A landmark study on Dsup protein showed that it can bind nucleosomes in the cell and protect DNA.[8]

The Dsup protein has been tested on other animal cells. Using a culture of human cells that express the Dsup protein, it was found that after X-ray exposure the cells had fewer DNA breaks than control cells.[2]

After hydrogen peroxide treatment Dsup+ cells mainly activate the detoxification systems and the antioxidant enzymes that limit oxidative stress and eliminate oxidative free radicals, while DNA repair mechanisms are only marginally activated.[9] Thus, upon induction of oxidative stress Dsup protein appears to mainly protect DNA directly.[9]

Function and structure

The Dsup from Ramazzottius varieornatus is mainly used for study, since it is one of the most stress-tolerant species. Orthologous versions of Dsup are also found in Hypsibius exemplaris (OQV24709, A0A1W0XB17). Dsup does not exhibit a lot of secondary structure, save for the helix in the middle. The C-terminal half contains an NLS, and this Ala/Gly-rich half is sufficient for DNA binding. It is probably mostly disordered, but it has a lot of positive charge.[1]

Dsup is known to bind to free DNA, but it binds more tightly to nucleosomes, the typical packed form of DNA in eukaryotic cells. Its nucleosome binding domain is vaguely similar to the one in HMGN proteins.[10]

Molecular dynamic simulation of Dsup in complex with DNA shows that it is an intrinsically disordered protein. Its flexibility and electrostatic charge helps it bind to DNA and form aggregates.[11]

References
  1. Hashimoto T, Kunieda T (June 2017). "DNA Protection Protein, a Novel Mechanism of Radiation Tolerance: Lessons from Tardigrades". Life. 7 (2): 26. Bibcode:2017Life....7...26H. doi:10.3390/life7020026. PMC 5492148. PMID 28617314.
  2. Turk V (20 September 2016). "Scientists Identify Gene That Protects Tardigrades From Radiation". Vice. Retrieved 19 May 2018.
  3. Tauger N, Gill V (20 September 2016). "Survival secret of 'Earth's hardiest animal' revealed". BBC News. Retrieved 2016-09-21.
  4. Hashimoto T, Horikawa DD, Saito Y, Kuwahara H, Kozuka-Hata H, Shin-I T, et al. (September 2016). "Extremotolerant tardigrade genome and improved radiotolerance of human cultured cells by tardigrade-unique protein". Nature Communications. 7: 12808. Bibcode:2016NatCo...712808H. doi:10.1038/ncomms12808. PMC 5034306. PMID 27649274.
  5. Horikawa DD, Sakashita T, Katagiri C, Watanabe M, Kikawada T, Nakahara Y, et al. (December 2006). "Radiation tolerance in the tardigrade Milnesium tardigradum". International Journal of Radiation Biology. 82 (12): 843–8. doi:10.1080/09553000600972956. PMID 17178624. S2CID 25354328.
  6. Horikawa DD, Sakashita T, Katagiri C, Watanabe M, Kikawada T, Nakahara Y, et al. (December 2006). "Radiation tolerance in the tardigrade Milnesium tardigradum". International Journal of Radiation Biology. 82 (12): 843–8. doi:10.1080/09553000600972956. PMID 17178624. S2CID 25354328.
  7. Horikawa, Daiki D. "UV Radiation Tolerance of Tardigrades". NASA.com. Archived from the original on 2013-02-18. Retrieved 2013-01-15.
  8. Chavez, Carolina; Cruz-Becerra, Grisel; Fei, Jia; Kassavetis, George A; Kadonaga, James T (2019-10-01). Jones, Katherine A; Tyler, Jessica K (eds.). "The tardigrade damage suppressor protein binds to nucleosomes and protects DNA from hydroxyl radicals". eLife. 8: e47682. doi:10.7554/eLife.47682. ISSN 2050-084X. PMC 6773438. PMID 31571581.
  9. Ricci, C.; Riolo, G.; Marzocchi, C.; Brunetti, J.; Pini, A.; Cantara, S. (2021). "The Tardigrade Damage Suppressor Protein Modulates Transcription Factor and DNA Repair Genes in Human Cells Treated with Hydroxyl Radicals and UV-C". Biology. 10 (10): 970. doi:10.3390/biology10100970. PMC 8533384. PMID 34681069.
  10. Chavez C, Cruz-Becerra G, Fei J, Kassavetis GA, Kadonaga JT (October 2019). "The tardigrade damage suppressor protein binds to nucleosomes and protects DNA from hydroxyl radicals". eLife. 8. doi:10.7554/eLife.47682. PMC 6773438. PMID 31571581.
  11. Mínguez-Toral M, Cuevas-Zuviría B, Garrido-Arandia M, Pacios LF (August 2020). "A computational structural study on the DNA-protecting role of the tardigrade-unique Dsup protein". Scientific Reports. 10 (1): 13424. Bibcode:2020NatSR..1013424M. doi:10.1038/s41598-020-70431-1. PMC 7414916. PMID 32770133.
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