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This is an old revision of this page, as edited by Horrockssam (talk | contribs) at 18:29, 24 October 2017 (Chem 455 Peer Review). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Chi-Wen's Peer Review [CHEM 455]

Overall, I think you did a good job on the new version of this page.

One thing that I would recommend is in the section of application.

1. To make this paragraph more organized, I would recommend adding subtopics and talk different applications separately (experimental methods and clinical treatments).

2. This paragraph has less information, I would recommend finding more review papers or reports regarding the techniques (introducing in vivo and in vitro Protein-DNA crosslinking) and clinical treatments (reference any news regarding the clinical applications)

Sam Horrocks's Peer Review [Chem 455/505]

Like Chin Wen, I agree that overall you've done a very good job adding to this page.

Also though, I have a few suggestions in the Applications section:

  1. What exactly is photocrosslinking? You mentioned it in the first paragraph, but never explained it?
  2. Also, there are a few grammar things that would need to be touched up. For example, in the second sentence of the second paragraph, you say, "Cancer treatment have been..." but it should be "Cancer treatments have been..."

In genetics, crosslinking of DNA occurs when various exogenous or endogenous agents react with two nucleotides of DNA, forming a covalent linkage between them. This crosslink can occur within the same strand (intrastrand) or between opposite strands of double-stranded DNA (interstrand). These adducts intefere with cellular metabolism, such as DNA replication and Transcription, triggering cell death. These crosslinks can, however, be repaired through excision or recombination pathways.

DNA crosslinking also has useful merit in chemotherapy and targeting cancerous cells for apoptosis, as well as in understanding how proteins interact with DNA.

Crosslinking agents

Many characterized crosslinking agents have two independently reactive groups within the same molecule, each of which is able to bind with a nucleotide residue of DNA. These agents are separated based upon their source of origin and labeled either as exogenous or endogenous. Exogenous crosslinking agents are chemicals and compounds, both natural and synthetic, that stem from enviromental exposures, such as pharmaceuticals and cigarette smoke or automotive exhaust. Endogenous crosslinking agents are compounds and metabolites that are introduced from cellular or biochemical pathways within a cell or organism.

Exogenous Agents

  • Nitrogen mustards are exogenous alkylating agents which react with the N7 position of guanine. These compounds have a bis-(2-ethylchloro)amine core structure, with a variable R-group, with the two reactive functional groups serving to alkylate nucleobases and form a crosslink lesion. These agents most preferentially form a 1,3 5'-d(GNC) interstrand crosslink. The introduction of this agent slightly bends the DNA duplex to accommodate for the agent's presence within the helix.[1] These agents are often introduced as a pharmaceutical and are used in cytotoxic chemotherapy.[2]
  • Cisplatin (cis-diamminedichloroplatinum(II)) and its derivatives mostly act on adjacent guanines at their N7 positions. The planar compound links to nucleobases through water displacement of one or both of its chloride groups, allowing cisplatin to form monoadducts to DNA or RNA, intrastrand DNA crosslinks, interstrand DNA crosslinks, and DNA-protein crosslinks[3]. When cisplatin generates DNA crosslinks, it more frequenlty forms 1,2-intrastrand crosslinks (5'-GG), but also forms 1,3-intrastrand crosslinks (5-GNG) at lower percentages.[4][5] When cisplatin forms interstrand crosslinks (5'-GC), there is a severe distortion to the DNA helix due to a shortened distance between guanines on opposite strands and a cytosine that is flipped out of the helix as a consequence of the GG interaction.[6] Similar to nitrogen mustards, cisplatin is used frequently in chemotherapy treatment - especially for testicular and ovarian cancers.[7]
  • Chloro ethyl nitroso urea (CENU), specifically carmustine (BCNU), are crosslinking agents that are widely used in chemotherapy, particularly for brain tumors. These agents differ from other crosslinkers as they alkylate O6 of guanine to form an O6-ethanoguanine. This intermediate compound then leads to an interstrand crosslink between a GC basepair. These crosslinking agents only result in small distortions to the DNA helix due to the molecules' smaller size.
  • Psoralens are natural compounds (furocoumarins) present in plants. These compounds intercalate into DNA at 5'-AT sequence sites and form thymidine adducts when activated in the presence of UV - A.[8] These covalent adducts are formed by linking the 3, 4 (pyrone) or 4', 5’ (furan) edge of psoralen to the 5, 6 double bond of thymine. Psoralens can form two types of monoadducts and one diadduct (an interstrand crosslink) with thymine.[9] These adducts result in local distortions to DNA at the site of intercalation. Psoralens are used in the medical treatment of skin diseases, such as psoriasis and vitiligo.

DNA damage induced by ionizing radiation is similar to that of oxidative stress, and these lesions have been implicated in aging and cancer. Biological effects of single-base damage by radiation or oxidation, such as 8-oxoguanine and thymine glycol, have been extensively studied. Recently the focus has shifted to some of the more complex lesions. Tandem DNA lesions are formed at a substantial frequency by ionizing radiation and metal-catalyzed H2O2 reactions. Under anoxic conditions, the predominant double-base lesion is a species in which the C8 of guanine is linked to the 5-methyl group of an adjacent 3'-thymine (G[8,5- Me]T).[10]

Endogenous Agents

  • Nitrous acid is formed in the stomach from dietary sources of nitrites. It induces formation of interstrand DNA crosslinks at the aminogroup of exocyclic N2 of guanine at CG sequences.
  • Bifunctional aldehydes are reactive chemicals that are formed endogenously via lipid peroxidation and prostoglandin biosynthesis.[11] They create etheno adducts formed by aldehyde which undergo rearrangements to form crosslinks on opposite strands of DNA. Malondialdehyde is a prototypical example that can crosslink DNA via two exocylcic guanine amino groups.[12] Other aldehydes, such as formaldehyde and acetylaldehyde, can introduce interstrand crosslinks and often act as exogenous agents as they are found in many processed foods. Often found within pesticides, tobacco smoke, and automotive exhaust, α,β unsaturated aldehydes, such as acrolein and crotonaldehyde, are further exogenous agents that may induce DNA crosslinks. Unlike other crosslinking agents, aldehyde-induced crosslinking is a intrinsically reversible process. NMR structure of these types of agents as interstrand crosslinks show that a 5'-GC adduct results in minor distortion to DNA, however a 5'-CG adduct destabilizes the helix and induces a bend and twist in the DNA.[13]

Crosslinked DNA is repaired in cells by a combination of enzymes and other factors from the nucleotide excision repair (NER) pathway, homologous recombination, and the base excision repair (BER) pathway.To repair interstrand crosslinks in eukaryotes, a 3’ flap endonuclease from the NER, XPF-ERCC1, is recruited to the crosslinked DNA, where it assists in ‘unhooking’ the DNA by cleaving the 3’ strand at the crosslink site. The 5’ strand is then cleaved, either by XPF-ERCC1 or another endonuclease, forming a double-strand break (DSB), which can then be repaired by the homologous recombination pathway.[14]

DNA crosslinks generally cause loss of overlapping sequence information from the two strands of DNA. Therefore, accurate repair of the damage depends on retrieving the lost information from an undamaged homologous chromosome in the same cell. Retrieval can occur by pairing with a sister chromosome produced during a preceding round of replication. In a diploid cell retrieval may also occur by pairing with a non-sister homologous chromosome, as occurs especially during meiosis.[15] Once pairing has occurred, the crosslink can be removed and correct information introduced into the damaged chromosome by homologous recombination.

Cleavage of the bond between a deoxyribose sugar in DNA’s sugar-phosphate backbone and its associated nucleobase leaves an abasic site in double stranded DNA. These abasic sites are often generated as an intermediate and then restored in base excision repair. However, if these sites are allowed to persist, they can inhibit DNA replication and transcription.[16] Abasic sites can react with amine groups on proteins to form DNA-protein crosslinks or with exocyclic amines of other nucleobases to form interstrand crosslinks. To prevent interstrand or DNA-protein crosslinks, enzymes from the BER pathway tightly bind the abasic site and sequester it from nearby reactive groups, as demonstrated in human alkyladenine DNA glycosylase (AAG) and E. coli 3-methyladenine DNA glycosylase II (AlkA).[17]

Treatment of E. coli with psoralen-plus-UV light (PUVA) produces interstrand crosslinks in the cells’ DNA. Cole et al.[18] and Sinden and Cole[19] presented evidence that an homologous recombinational repair process requiring the products of genes uvrA, uvrB, and recA can remove these crosslinks in E. coli. This process appears to be quite efficient. Even though one or two unrepaired crosslinks are sufficient to inactivate a cell, a wild-type bacterial cell can repair and therefore recover from 53 to 71 psoralen crosslinks. Eukaryotic yeast cells are also inactivated by one remaining crosslink, but wild type yeast cells can recover from 120 to 200 crosslinks.[20]

In humans, the leading cause of cancer deaths worldwide is lung cancer, including non small cell lung carcinoma (NSLC) which accounts for 85% of all lung cancer cases in the United States.[21] Individuals with NSLC are often treated with therapeutic platinum compounds (e.g. cisplatin, carboplatin or oxaliplatin) (see Lung cancer chemotherapy) that cause inter-strand DNA crosslinks. Among individuals with NSLC, low expression of BRCA1 in the primary tumor correlated with improved survival after platinum-containing chemotherapy.[22][23] This correlation implies that low BRCA1 in the cancer, and the consequent low level of DNA repair, causes vulnerability of the cancer to treatment by the DNA crosslinking agents. High BRCA1 may protect cancer cells by acting in the homologous recombinational repair pathway that removes the damages in DNA introduced by the platinum drugs. Taron et al.[22] and Papadaki et al.[23] concluded that the level of BRCA1 expression is a potentially important tool for tailoring chemotherapy in lung cancer management.

Applications

Crosslinking of DNA and Protein

Similar to DNA crosslinking, DNA-protein crosslinks are lesions in cells that have been damaged by UV radiation. These crosslinks primarily occur in areas of the chromosomes that are undergoing DNA replication. The UV’s effect can lead to reactive interactions and cause DNA and the proteins that are in contact with it to crosslink. The structure of DNA-protein complexes can be mapped by photocrosslinking.

DNA repair pathways can result in the formation of tumor cells. Cancer treatment have been engineered using DNA cross-linking agents to interact with nitrogenous bases of DNA to block DNA replication. These cross-linking agents have the ability to act as single-agent therapies by targeting and destroying specific nucleotides in cancerous cells. This result is stopping the cycle and growth of cancer cells; because it inhibits specific DNA repair pathways, this approach has a potential advantage in having fewer side effects.

References

  1. ^ Guainazzi, Angelo; Schärer, Orlando D. (2010-11-01). "Using synthetic DNA interstrand crosslinks to elucidate repair pathways and identify new therapeutic targets for cancer chemotherapy". Cellular and Molecular Life Sciences. 67 (21): 3683–3697. doi:10.1007/s00018-010-0492-6. ISSN 1420-682X.
  2. ^ Cancer, Cleveland Clinic. "Nitrogen Mustard - Chemotherapy Drugs - Chemocare". chemocare.com. Retrieved 2017-10-09.
  3. ^ Jamieson, E. R.; Lippard, S. J. (1999-09-08). "Structure, Recognition, and Processing of Cisplatin-DNA Adducts". Chemical Reviews. 99 (9): 2467–2498. ISSN 1520-6890. PMID 11749487.
  4. ^ Poklar N, Pilch DS, Lippard SJ, Redding EA, Dunham SU, Breslauer KJ (July 1996). "Influence of cisplatin intrastrand crosslinking on the conformation, thermal stability, and energetics of a 20-mer DNA duplex". Proc. Natl. Acad. Sci. U.S.A. 93 (15): 7606–11. doi:10.1073/pnas.93.15.7606. PMC 38793. PMID 8755522.
  5. ^ Rudd GN, Hartley JA, Souhami RL (1995). "Persistence of cisplatin-induced DNA interstrand crosslinking in peripheral blood mononuclear cells from elderly and young individuals". Cancer Chemother. Pharmacol. 35 (4): 323–6. doi:10.1007/BF00689452. PMID 7828275.
  6. ^ Coste, F.; Malinge, J. M.; Serre, L.; Shepard, W.; Roth, M.; Leng, M.; Zelwer, C. (1999-04-15). "Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 A resolution: hydration at the platinated site". Nucleic Acids Research. 27 (8): 1837–1846. ISSN 0305-1048. PMID 10101191.
  7. ^ "Cisplatin". National Cancer Institute. Retrieved 2017-10-09.
  8. ^ Cimino, G. D.; Gamper, H. B.; Isaacs, S. T.; Hearst, J. E. (1985). "Psoralens as photoactive probes of nucleic acid structure and function: organic chemistry, photochemistry, and biochemistry". Annual Review of Biochemistry. 54: 1151–1193. doi:10.1146/annurev.bi.54.070185.005443. ISSN 0066-4154. PMID 2411210.
  9. ^ Qi Wu, Laura A Christensen, Randy J Legerski & Karen M Vasquez, Mismatch repair participates in error-free processing of DNA interstrand crosslinks in human cells,EMBO reports 6, 6, 551–557 (2005).
  10. ^ LC Colis; P Raychaudhury; AK Basu (2008). "Mutational specificity of gamma-radiation-induced guanine-thymine and thymine-guanine intrastrand cross-links in mammalian cells and translesion synthesis past the guanine-thymine lesion by human DNA polymerase eta". Biochemistry. 47 (6): 8070–8079. doi:10.1021/bi800529f. PMC 2646719. PMID 18616294.
  11. ^ Stone, Michael P.; Cho, Young-Jin; Huang, Hai; Kim, Hye-Young; Kozekov, Ivan D.; Kozekova, Albena; Wang, Hao; Minko, Irina G.; Lloyd, R. Stephen (2008-07-01). "Interstrand DNA Cross-Links Induced by α,β-Unsaturated Aldehydes Derived from Lipid Peroxidation and Environmental Sources". Accounts of Chemical Research. 41 (7): 793–804. doi:10.1021/ar700246x. ISSN 0001-4842.
  12. ^ Niedernhofer, Laura J.; Daniels, J. Scott; Rouzer, Carol A.; Greene, Rachel E.; Marnett, Lawrence J. (2003-08-15). "Malondialdehyde, a Product of Lipid Peroxidation, Is Mutagenic in Human Cells". Journal of Biological Chemistry. 278 (33): 31426–31433. doi:10.1074/jbc.m212549200. ISSN 0021-9258. PMID 12775726.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ Dooley, Patricia A.; Zhang, Mingzhou; Korbel, Gregory A.; Nechev, Lubomir V.; Harris, Constance M.; Stone, Michael P.; Harris, Thomas M. (2003-01-08). "NMR determination of the conformation of a trimethylene interstrand cross-link in an oligodeoxynucleotide duplex containing a 5'-d(GpC) motif". Journal of the American Chemical Society. 125 (1): 62–72. doi:10.1021/ja0207798. ISSN 0002-7863. PMID 12515507.
  14. ^ Klein Douwel, Daisy; Boonen, Rick A.C.M.; Long, David T.; Szypowska, Anna A.; Räschle, Markus; Walter, Johannes C.; Knipscheer, Puck. "XPF-ERCC1 Acts in Unhooking DNA Interstrand Crosslinks in Cooperation with FANCD2 and FANCP/SLX4". Molecular Cell. 54 (3): 460–471. doi:10.1016/j.molcel.2014.03.015.
  15. ^ Harris Bernstein, Carol Bernstein and Richard E. Michod (2011). Meiosis as an Evolutionary Adaptation for DNA Repair. Chapter 19 pages 357-382 in “DNA Repair” (Inna Kruman editor). InTech Open Publisher. DOI: 10.5772/25117 ISBN 978-953-307-697-3 http://www.intechopen.com/books/dna-repair/meiosis-as-an-evolutionary-adaptation-for-dna-repair
  16. ^ DNA repair and mutagenesis. Friedberg, Errol C., Friedberg, Errol C. (2nd ed ed.). Washington, D.C.: ASM Press. 2006. ISBN 9781555813192. OCLC 59360087. {{cite book}}: |edition= has extra text (help)CS1 maint: others (link)
  17. ^ Admiraal, Suzanne J.; O’Brien, Patrick J. (2015-03-10). "Base Excision Repair Enzymes Protect Abasic Sites in Duplex DNA from Interstrand Cross-Links". Biochemistry. 54 (9): 1849–1857. doi:10.1021/bi501491z. ISSN 0006-2960.
  18. ^ Cole RS, Levitan D, Sinden RR (1976). "Removal of psoralen interstrand cross-links from DNA of Escherichia coli: mechanism and genetic control". J. Mol. Biol. 103 (1): 39–59. doi:10.1016/0022-2836(76)90051-6. PMID 785009.
  19. ^ Sinden RR, Cole RS (1978). "Repair of cross-linked DNA and survival of Escherichia coli treated with psoralen and light: effects of mutations influencing genetic recombination and DNA metabolism". J. Bacteriol. 136 (2): 538–47. PMC 218577. PMID 361714.
  20. ^ Noll DM, Mason TM, Miller PS (2006). "Formation and repair of interstrand cross-links in DNA". Chem. Rev. 106 (2): 277–301. doi:10.1021/cr040478b. PMC 2505341. PMID 16464006.
  21. ^ Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA (2008). "Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship". Mayo Clin. Proc. 83 (5): 584–94. doi:10.4065/83.5.584. PMC 2718421. PMID 18452692.
  22. ^ a b Taron M, Rosell R, Felip E, Mendez P, Souglakos J, Ronco MS, Queralt C, Majo J, Sanchez JM, Sanchez JJ, Maestre J (2004). "BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer". Hum. Mol. Genet. 13 (20): 2443–9. doi:10.1093/hmg/ddh260. PMID 15317748.
  23. ^ a b Papadaki C, Sfakianaki M, Ioannidis G, Lagoudaki E, Trypaki M, Tryfonidis K, Mavroudis D, Stathopoulos E, Georgoulias V, Souglakos J (2012). "ERCC1 and BRAC1 mRNA expression levels in the primary tumor could predict the effectiveness of the second-line cisplatin-based chemotherapy in pretreated patients with metastatic non-small cell lung cancer". J Thorac Oncol. 7 (4): 663–71. doi:10.1097/JTO.0b013e318244bdd4. PMID 22425915.
  • PDB: 1AIO​ - Interactive structure for cisplatin and DNA adduct formation
  • PDB: 204D​ - Interactive structure for psoralen and crosslinked DNA
  • Psoralen Ultraviolet A Light Treatment [1]
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