Dsup

Last updated
Damage suppressor protein
Identifiers
Organism Ramazzottius varieornatus (tardigrade)
SymbolDsup
UniProt P0DOW4
Search for
Structures Swiss-model
Domains InterPro

Dsup (contraction of damage suppressor) is a DNA-associating protein, unique to the tardigrade, [1] that suppresses the occurrence of DNA breaks by radiation. [2] [3] [4] [5] When human HEK293 cells were engineered with Dsup proteins, they showed approximately 40% more tolerance against X-ray radiation. [5]

Tardigrades can withstand 1,000 times more radiation than other animals, [6] 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. [3]

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]

Dsup protein has been found to be neurotoxic and promote neurodegeneration when expressed in cultured neurons by increasing DNA damage through the formation of double strand breaks. [10]

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. [2]

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. [11]

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. [12]

Related Research Articles

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O₂)

In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH.), and singlet oxygen. ROS are pervasive because they are readily produced from O2, which is abundant. ROS are important in many ways, both beneficial and otherwise. ROS function as signals, that turn on and off biological functions. They are intermediates in the redox behavior of O2, which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however, ROS are discussed in a biological context, ranging from their effects on aging and their role in causing dangerous genetic mutations.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.

<span class="mw-page-title-main">Molecular lesion</span> Damage to the structure of a biological molecule

A molecular lesion or point lesion is damage to the structure of a biological molecule such as DNA, RNA, or protein. This damage may result in the reduction or absence of normal function, and in rare cases the gain of a new function. Lesions in DNA may consist of breaks or other changes in chemical structure of the helix, ultimately preventing transcription. Meanwhile, lesions in proteins consist of both broken bonds and improper folding of the amino acid chain. While many nucleic acid lesions are general across DNA and RNA, some are specific to one, such as thymine dimers being found exclusively in DNA. Several cellular repair mechanisms exist, ranging from global to specific, in order to prevent lasting damage resulting from lesions.

Radioresistance is the level of ionizing radiation that organisms are able to withstand.

HMGN proteins are members of the broader class of high mobility group (HMG) chromosomal proteins that are involved in regulation of transcription, replication, recombination, and DNA repair.

DNA footprinting is a method of investigating the sequence specificity of DNA-binding proteins in vitro. This technique can be used to study protein-DNA interactions both outside and within cells.

The family of heterochromatin protein 1 (HP1) consists of highly conserved proteins, which have important functions in the cell nucleus. These functions include gene repression by heterochromatin formation, transcriptional activation, regulation of binding of cohesion complexes to centromeres, sequestration of genes to the nuclear periphery, transcriptional arrest, maintenance of heterochromatin integrity, gene repression at the single nucleosome level, gene repression by heterochromatization of euchromatin, and DNA repair. HP1 proteins are fundamental units of heterochromatin packaging that are enriched at the centromeres and telomeres of nearly all eukaryotic chromosomes with the notable exception of budding yeast, in which a yeast-specific silencing complex of SIR proteins serve a similar function. Members of the HP1 family are characterized by an N-terminal chromodomain and a C-terminal chromoshadow domain, separated by a hinge region. HP1 is also found at some euchromatic sites, where its binding can correlate with either gene repression or gene activation. HP1 was originally discovered by Tharappel C James and Sarah Elgin in 1986 as a factor in the phenomenon known as position effect variegation in Drosophila melanogaster.

Postreplication repair is the repair of damage to the DNA that takes place after replication.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">Evelyn M. Witkin</span> American geneticist (1921–2023)

Evelyn M. Witkin was an American bacterial geneticist at Cold Spring Harbor Laboratory (1944–1955), SUNY Downstate Medical Center (1955–1971), and Rutgers University (1971–1991). Witkin was considered innovative and inspirational as a scientist, teacher and mentor.

<span class="mw-page-title-main">CUL4A</span> Protein-coding gene in humans

Cullin-4A is a protein that in humans is encoded by the CUL4A gene. CUL4A belongs to the cullin family of ubiquitin ligase proteins and is highly homologous to the CUL4B protein. CUL4A regulates numerous key processes such as DNA repair, chromatin remodeling, spermatogenesis, haematopoiesis and the mitotic cell cycle. As a result, CUL4A has been implicated in several cancers and the pathogenesis of certain viruses including HIV. A component of a CUL4A complex, Cereblon, was discovered to be a major target of the teratogenic agent thalidomide.

<span class="mw-page-title-main">DDB2</span> Protein-coding gene in the species Homo sapiens

DNA damage-binding protein 2 is a protein that in humans is encoded by the DDB2 gene.

<span class="mw-page-title-main">RNF8</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene. RNF8 has activity both in immune system functions and in DNA repair.

<span class="mw-page-title-main">Tardigrade</span> Phylum of microscopic animals, also known as water bears

Tardigrades, known colloquially as water bears or moss piglets, are a phylum of eight-legged segmented micro-animals. They were first described by the German zoologist Johann August Ephraim Goeze in 1773, who called them Kleiner Wasserbär. In 1777, the Italian biologist Lazzaro Spallanzani named them Tardigrada, which means "slow steppers".

<i>Deinococcus radiodurans</i> Radioresistant extremophile species of bacterium

Deinococcus radiodurans is a bacterium, an extremophile and one of the most radiation-resistant organisms known. It can survive cold, dehydration, vacuum, and acid, and therefore is known as a polyextremophile. The Guinness Book Of World Records listed it as the world's toughest known bacterium.

<i>Hypsibius dujardini</i> Species of tardigrade

Hypsibius dujardini sensu lato is a species complex of tardigrade in the class Eutardigrada. A member of this complex, Hypsibius exemplaris, is widely used for various research projects pertaining to evolutionary biology and astrobiology.

DNA damage-binding protein or UV-DDB is a protein complex that is responsible for repair of UV-damaged DNA. This complex is composed of two protein subunits, a large subunit DDB1 (p127) and a small subunit DDB2 (p48). When cells are exposed to UV radiation, DDB1 moves from the cytosol to the nucleus and binds to DDB2, thus forming the UV-DDB complex. This complex formation is highly favorable and it is demonstrated by UV-DDB's binding preference and high affinity to the UV lesions in the DNA. This complex functions in nucleotide excision repair, recognising UV-induced (6-4) pyrimidine-pyrimidone photoproducts and cyclobutane pyrimidine dimers.

<i>Ramazzottius</i> Genus of tardigrades

Ramazzottius is a genus of water bear or moss piglet, a tardigrade in the class Eutardigrada.

<span class="mw-page-title-main">Retinoblastoma protein</span> Mammalian protein found in Homo sapiens

The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, inactivating it, and the cell cycle is allowed to progress. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.

DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a nucleobase missing from the backbone of DNA, or a chemically changed base such as 8-OHdG. DNA damage can occur naturally or via environmental factors, but is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of base pairs. DNA damages cause changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly. The DNA damage response (DDR) is a complex signal transduction pathway which recognizes when DNA is damaged and initiates the cellular response to the damage.

References

  1. ↑ Zimmer C (12 April 2024). "What Makes Tiny Tardigrades Nearly Radiation Proof - New research finds that the microscopic "water bears" are remarkably good at repairing their DNA after a huge blast of radiation". The New York Times . Archived from the original on 12 April 2024. Retrieved 13 April 2024.
  2. 1 2 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.
  3. 1 2 Turk V (20 September 2016). "Scientists Identify Gene That Protects Tardigrades From Radiation". Vice . Retrieved 19 May 2018.
  4. ↑ Tauger N, Gill V (20 September 2016). "Survival secret of 'Earth's hardiest animal' revealed". BBC News. Retrieved 2016-09-21.
  5. 1 2 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.
  6. 1 2 3 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): 843–848. doi:10.1080/09553000600972956. PMID   17178624. S2CID   25354328.
  7. ↑ Horikawa DD. "UV Radiation Tolerance of Tardigrades". NASA.com. Archived from the original on 2013-02-18. Retrieved 2013-01-15.
  8. ↑ Chavez C, Cruz-Becerra G, Fei J, Kassavetis GA, Kadonaga JT (October 2019). Jones KA, Tyler JK (eds.). "The tardigrade damage suppressor protein binds to nucleosomes and protects DNA from hydroxyl radicals". eLife. 8: e47682. doi: 10.7554/eLife.47682 . PMC   6773438 . PMID   31571581.
  9. 1 2 Ricci C, Riolo G, Marzocchi C, Brunetti J, Pini A, Cantara S (September 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. ↑ Escarcega RD, Patil AA, Meyer MD, Moruno-Manchon JF, Silvagnoli AD, McCullough LD, et al. (June 2023). "The Tardigrade damage suppressor protein Dsup promotes DNA damage in neurons". Molecular and Cellular Neurosciences. 125: 103826. doi:10.1016/j.mcn.2023.103826. PMC  10247392. PMID   36858083.
  11. ↑ 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.
  12. ↑ 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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.