DNA damage

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A DNA damage or DNA damage is a change in the chemical structure of DNA , which in the course of replication is not copied.

properties

Damage to the DNA leads to activation of DNA repair in order to restore the previous state. However, since not every repair restores the original condition, damage to DNA can cause mutations that, in certain combinations, lead to the development of cancer , e.g. B. if the mutations lead to activation of oncogenes or to inactivation of tumor suppressor genes . In healthy cells, DNA damage via the p53 protein can arrest cell division and lead to apoptosis , which limits the mutation rate in an organism.

Emergence

DNA damage can result from ionizing radiation (e.g. UV, X-ray, gamma radiation), oxidation , hydrolysis , mutagens (including the alkylating agents and DNA crosslinking agents ). By inserting some oncoviruses into the genome of their host cell, genes can be changed. In addition, errors in a DNA sequence are sometimes caused by errors in replication . Damage can occur both to the nucleobases and to the DNA backbone ( deoxyribose and phosphate ). About 60,000 DNA damage occurs in a mammalian cell every day. Ionizing radiation performs a radiolysis of water to form hydroxide - radicals which can oxidize other molecules in their vicinity. In addition, some DNA damage can also occur in the course of the metabolism without external influence (endogenous).

Frequencies of endogenous DNA damage in mammals
Endogenous DNA damage Number per cell
Abasic passages 30,000
N 7- (2-hydroxethyl) guanine (7HEG) 3,000
8-hydroxyguanine 2,400
7- (2-oxoethyl) guanine 1,500
Formaldehyde adducts 960
Acrolein deoxyguanine 120
Malondialdehyde deoxyguanine 60

In rats, the number of abasic sites increases from around 50,000 per cell in the liver, kidneys and lungs to around 200,000 per cell in the brain. In young rats there are about 24,000 DNA adducts per cell, while in old rats there are 66,000 DNA adducts per cell. The increase in mutations is characteristic of aging .

Types

Photocyclization

When exposed to UV light, neighboring thymines react via a 2 + 2 cycloaddition , which simultaneously represents a photodimerization and a photocyclization .

oxidation

About 60 to 70% of DNA damage in mammalian cells is caused by oxidation. More than 100 oxidations of DNA have been described so far, of which the oxidation to 8-oxodG accounts for about 5% of the oxidation damage. Oxidations cause around 10,000 to 11,500 damage per day per human cell, of which around 2,800 damage of the type 8-oxoGua, 8-oxodG plus 5-HMUra. In rats, about 74,000 to 100,000 are produced per day per cell. In the cells of mice, between 28,000 and 47,000 damage of the type 8-oxoGua, 8-oxodG, 5-HMUra occurs.

By iron (II) - ion (or other transition metals ) hydroxide radicals can via the Fenton reaction are formed. The iron ions are oxidized to iron (III) ions. The regeneration (reduction) takes place via the Haber-Weiss reaction . Iron is the most common transition metal in most living things.

Formation of deoxyribonolactone

Hydroxide radicals can lead to the formation of a radical at the 1'-C atom of deoxyribose, which in turn forms a peroxide with oxygen , which rearranges to form 2'-deoxyribonolactone and releases the nucleobase, creating an abasic site in the DNA. The 2'-deoxyribonolactone is mutagenic and inhibits DNA repair.

Hydroxide radicals can also add to the π electrons of certain double bonds in nucleic bases, including at C5-C6 of pyrimidines and N7-C8 in purines . In addition, hydroxide radicals can add to various other atoms in DNA.

Depurination

Depurinations occur around 2,000 to 14,000 per mammalian cell.

Depyrimidation

Depyrimidation occurs in a mammalian cell about 600 to 700 times a day.

Strand breaks

A single strand break occurs approximately 55,200 times per day per mammalian cell. Within the ribose, hydroxyl radicals prefer 5 ′ H> 4 ′ H> 3 ′ H ≈ 2 ′ H ≈ 1 ′ H as reaction partner, which can lead to strand breakage.

A double-strand break occurs about 10 to 50 times per cell division per human cell.

Methylation

O6-methylguanine is produced around 3,120 times a day in a mammalian cell. The deamination of cytosine happens about 192 times a mammalian cell per day. In addition, M1dG (3- (2'-deoxy-β- D -erythro-pentofuranosyl) -pyrimido [1,2- a ] -purine-10 (3 H ) -one) can also be formed. M1G and 8-oxodG are mutagenic for their part .

Other DNA adducts

Different DNA adducts can be formed by mutagens .

Individual evidence

  1. ↑ a b Clark Chen, Carol Bernstein, Anil R. Prasad, Valentine Nfonsam, Harris Bernstein: New Research Directions in DNA Repair . Chapter 16: DNA Damage, DNA Repair and Cancer. ISBN 978-953-511-114-6 .
  2. ↑ Sung-Lim Yu, Sung-Keun Lee: Ultraviolet radiation: DNA damage, repair, and human disorders. In: Molecular & Cellular Toxicology . 13, 2017, p. 21, doi: 10.1007 / s13273-017-0002-0 .
  3. ↑ JA Swenberg, K. Lu, BC Moeller, L. Gao, PB Upton, J. Nakamura, TB Starr: Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment. In: Toxicol Sci. 120 (Suppl 1), 2011, pp. S130-S145. PMID 21163908
  4. ↑ J. Nakamura, JA Swenberg: Endogenous apurinic / apyrimidinic sites in genomic DNA of mammalian tissues. In: Cancer Research . 59 (11), 1999, pp. 2522-2526. PMID 10363965
  5. ↑ a b c H. J. Helbock, KB Beckman, MK Shigenaga, PB Walter, AA Woodall, HC Yeo, BN Ames: DNA oxidation matters: The HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine . In: Proceedings of the National Academy of Sciences USA . tape 95 , no. 1 , January 6, 1998, ISSN  0027-8424 , p. 288-293 , doi : 10.1073 / pnas.95.1.288 , PMID 9419368 , PMC 18204 (free full text).
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  7. ↑ ML Hamilton, Z. Guo, CD Fuller, H. Van Remmen, WF Ward, SN Austad, DA Troyer, I. Thompson, A. Richardson: A reliable assessment of 8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA. In: Nucleic Acids Res. 29 (10), 2001, pp. 2117-2126. PMID 11353081 .
  8. ↑ a b B. N. Ames, MK Shigenaga, TM Hagen: Oxidants, antioxidants, and the degenerative diseases of aging. In: Proceedings of the National Academy of Sciences USA . tape 90 , no. 17 , September 1, 1993, ISSN  0027-8424 , p. 7915-7922 , doi : 10.1073 / pnas.90.17.7915 , PMID 8367443 , PMC 47258 (free full text).
  9. ↑ a b M. Foksinski, R. Rozalski, J. Guz, B. Ruszkowska, P. Sztukowska, M. Piwowarski, A. Klungland, R. Olinski: Urinary excretion of DNA repair products correlates with metabolic rates as well as with maximum life spans of different mammalian species. In: Free Radic Biol Med. 37 (9), 2004, pp. 1449-1454. PMID 15454284 .
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  12. ↑ ML Hamilton, Z. Guo, CD Fuller, H. Van Remmen, WF Ward, SN Austad, DA Troyer, I. Thompson, A. Richardson: A reliable assessment of 8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA. In: Nucleic Acids Res. 29 (10), 2001, pp. 2117-2126. PMID 11353081 .
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  16. ↑ Steen Steenken: Purine bases, nucleosides, and nucleotides: aqueous solution redox chemistry and transformation reactions of their radical cations and e and OH adducts. In: Chemical Reviews. 89, 1989, pp. 503-520, doi: 10.1021 / cr00093a003 .
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  20. ↑ a b T. Lindahl: DNA repair enzymes acting on spontaneous lesions in DNA. In: WW Nichols, DG Murphy (Ed.): DNA Repair Processes. Symposia Specialists, Miami 1977, ISBN 0-88372-099-X , pp. 225-240.
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  27. ↑ LA Vander-Veen, MF Hashim, Y. Shyr, LJ Marnett: Induction of frameshift and base pair substitution mutations by the major DNA adduct of the endogenous carcinogen malondialdehyde. In: Proc Natl Acad Sci U.S.A. 100 (24), 2003, pp. 14247-14252. PMID 14603032
  28. ↑ X. Tan, AP Grollman, S. Shibutani: Comparison of the mutagenic properties of 8-oxo-7,8-dihydro-2'-deoxyadenosine and 8-oxo-7,8-dihydro-2'-deoxyguanosine DNA lesions in mammalian cells. In: Carcinogenesis. 20 (12), 1999, pp. 2287-2292. PMID 10590221