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Added Applications section and a subsection on the crosslinking of DNA and protein to tie into its cancer application
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Edited and added content (and references) to nitrogen mustards and cisplatin exogenous agents giving the emphasis of their crosslinking effects.
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==Crosslinking agents==
==Crosslinking agents==
Many characterized crosslinking agents have two independently reactive groups within the same molecule, each of which 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 [[nitrogen mustard]] and cigarette smoke or automotive exhaust. Endogenous crosslinking agents are compounds and metabolites that are introduced from cellular or chemical pathways within a cell or organism.
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 [[nitrogen mustard]] 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 ===
===Exogenous Agents ===
Nitrogen mustards are exogenous [[Alkylating antineoplastic agent|alkylating agents]] which react with the ''N<sup>7</sup>'' 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 also slightly bends the DNA duplex to accommodate for the agent's presence within the helix.<ref>{{Cite journal|last=Guainazzi|first=Angelo|last2=Schärer|first2=Orlando D.|date=2010-11-01|title=Using synthetic DNA interstrand crosslinks to elucidate repair pathways and identify new therapeutic targets for cancer chemotherapy|url=https://link.springer.com/article/10.1007/s00018-010-0492-6|journal=Cellular and Molecular Life Sciences|language=en|volume=67|issue=21|pages=3683–3697|doi=10.1007/s00018-010-0492-6|issn=1420-682X}}</ref> These agents are often introduced as a pharmaceutical and are used in [[Cytotoxicity|cytotoxic]] [[chemotherapy]].<ref>{{Cite web|url=http://chemocare.com/chemotherapy/drug-info/Nitrogen-Mustard.aspx|title=Nitrogen Mustard - Chemotherapy Drugs - Chemocare|last=Cancer|first=Cleveland Clinic|website=chemocare.com|language=en|access-date=2017-10-09}}</ref>
⚫
[[Alkylating antineoplastic agent|Alkylating agents]] such as 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU, [[carmustine]])) and [[nitrogen mustard]] which are used in [[chemotherapy]] can cross link with DNA at N7 position of [[guanine]] on the opposite strands forming interstrand crosslinks.<ref name="pmid7767897">{{cite journal |vauthors=Ali-Osman F, Rairkar A, Young P |title=Formation and repair of 1,3-bis-(2-chloroethyl)-1-nitrosourea and cisplatin induced total genomic DNA interstrand crosslinks in human glioma cells |journal=Cancer Biochem. Biophys. |volume=14 |issue=4 |pages=231–41 |date=January 1995 |pmid=7767897 |doi= |url=}}</ref>

[[Cisplatin]] (cis-diamminedichloroplatinum(II)) and its derivatives mostly act on adjacent guanines at their ''N<sup>7</sup>'' 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<ref>{{Cite journal|last=Jamieson|first=E. R.|last2=Lippard|first2=S. J.|date=1999-09-08|title=Structure, Recognition, and Processing of Cisplatin-DNA Adducts|url=https://www.ncbi.nlm.nih.gov/pubmed/11749487|journal=Chemical Reviews|volume=99|issue=9|pages=2467–2498|issn=1520-6890|pmid=11749487}}</ref>. 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.<ref name="pmid8755522" /><ref name="pmid7828275" /> 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.<ref>{{Cite journal|last=Coste|first=F.|last2=Malinge|first2=J. M.|last3=Serre|first3=L.|last4=Shepard|first4=W.|last5=Roth|first5=M.|last6=Leng|first6=M.|last7=Zelwer|first7=C.|date=1999-04-15|title=Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 A resolution: hydration at the platinated site|url=https://www.ncbi.nlm.nih.gov/pubmed/10101191|journal=Nucleic Acids Research|volume=27|issue=8|pages=1837–1846|issn=0305-1048|pmid=10101191}}</ref> Similar to nitrogen mustards, cisplatin is used frequently in chemotherapy treatment - especially for testicular and ovarian cancers.<ref>{{Cite web|url=https://www.cancer.gov/about-cancer/treatment/drugs/cisplatin|title=Cisplatin|website=National Cancer Institute|language=en|access-date=2017-10-09}}</ref>

⚫
such as 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU, [[carmustine]])) and [[nitrogen mustard]] which are used in [[chemotherapy]] can cross link with DNA at N7 position of [[guanine]] on the opposite strands forming interstrand crosslinks.<ref name="pmid7767897">{{cite journal |vauthors=Ali-Osman F, Rairkar A, Young P |title=Formation and repair of 1,3-bis-(2-chloroethyl)-1-nitrosourea and cisplatin induced total genomic DNA interstrand crosslinks in human glioma cells |journal=Cancer Biochem. Biophys. |volume=14 |issue=4 |pages=231–41 |date=January 1995 |pmid=7767897 |doi= |url=}}</ref>


[[Cisplatin]] (cis-diamminedichloroplatinum(II)) and its derivatives forms DNA cross links as monoadduct, interstrand crosslink, intrastrand crosslink or DNA protein crosslink. Mostly it acts on the adjacent N-7 guanine forming 1, 2 intrastrand crosslink.<ref name="pmid8755522">{{cite journal |vauthors=Poklar N, Pilch DS, Lippard SJ, Redding EA, Dunham SU, Breslauer KJ |title=Influence of cisplatin intrastrand crosslinking on the conformation, thermal stability, and energetics of a 20-mer DNA duplex |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue=15 |pages=7606–11 |date=July 1996 |pmid=8755522 |pmc=38793 |doi= 10.1073/pnas.93.15.7606|url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8755522}}</ref><ref name="pmid7828275">{{cite journal |vauthors=Rudd GN, Hartley JA, Souhami RL |title=Persistence of cisplatin-induced DNA interstrand crosslinking in peripheral blood mononuclear cells from elderly and young individuals |journal=Cancer Chemother. Pharmacol. |volume=35 |issue=4 |pages=323–6 |year=1995 |pmid=7828275 |doi= 10.1007/BF00689452|url=}}</ref>
[[Cisplatin]] (cis-diamminedichloroplatinum(II)) and its derivatives forms DNA cross links as monoadduct, interstrand crosslink, intrastrand crosslink or DNA protein crosslink. Mostly it acts on the adjacent N-7 guanine forming 1, 2 intrastrand crosslink.<ref name="pmid8755522">{{cite journal |vauthors=Poklar N, Pilch DS, Lippard SJ, Redding EA, Dunham SU, Breslauer KJ |title=Influence of cisplatin intrastrand crosslinking on the conformation, thermal stability, and energetics of a 20-mer DNA duplex |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=93 |issue=15 |pages=7606–11 |date=July 1996 |pmid=8755522 |pmc=38793 |doi= 10.1073/pnas.93.15.7606|url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=8755522}}</ref><ref name="pmid7828275">{{cite journal |vauthors=Rudd GN, Hartley JA, Souhami RL |title=Persistence of cisplatin-induced DNA interstrand crosslinking in peripheral blood mononuclear cells from elderly and young individuals |journal=Cancer Chemother. Pharmacol. |volume=35 |issue=4 |pages=323–6 |year=1995 |pmid=7828275 |doi= 10.1007/BF00689452|url=}}</ref>
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[[Aldehyde]]s such as [[acrolein]] and [[crotonaldehyde]] found in tobacco smoke or automotive exhaust can form DNA interstrand crosslinks in DNA. Guanine adducts of DNA can also react with protein. A [[Schiff base]] formation between protein and aldehyde causes this DNA protein interstrand link
[[Aldehyde]]s such as [[acrolein]] and [[crotonaldehyde]] found in tobacco smoke or automotive exhaust can form DNA interstrand crosslinks in DNA. Guanine adducts of DNA can also react with protein. A [[Schiff base]] formation between protein and aldehyde causes this DNA protein interstrand link


===Endogenous===
===Endogenous Agents===
* [[Nitrous acid]] is formed in the stomach from dietary sources of nitrites. It induces formation of interstrand DNA crosslinks at the [[amino]]group of exocyclic N<sup>2</sup> of guanine at CG sequences.
* [[Nitrous acid]] is formed in the stomach from dietary sources of nitrites. It induces formation of interstrand DNA crosslinks at the [[amino]]group of exocyclic N<sup>2</sup> of guanine at CG sequences.
* Reactive chemicals such as [[malondialdehyde]] are formed endogenously as the product of [[lipid peroxidation]]. They create etheno adducts formed by [[aldehyde]] which undergo rearrangements to form crosslinks on opposite strands.<ref>Mathews & Vanholde, Biochemistry, 2nd Edition. Benjamin Cummings Publication</ref>
* Reactive chemicals such as [[malondialdehyde]] are formed endogenously as the product of [[lipid peroxidation]]. They create etheno adducts formed by [[aldehyde]] which undergo rearrangements to form crosslinks on opposite strands.<ref>Mathews & Vanholde, Biochemistry, 2nd Edition. Benjamin Cummings Publication</ref>

Revision as of 16:57, 9 October 2017

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 nitrogen mustard 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 also 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]

such as 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU, carmustine)) and nitrogen mustard which are used in chemotherapy can cross link with DNA at N7 position of guanine on the opposite strands forming interstrand crosslinks.[8]

Cisplatin (cis-diamminedichloroplatinum(II)) and its derivatives forms DNA cross links as monoadduct, interstrand crosslink, intrastrand crosslink or DNA protein crosslink. Mostly it acts on the adjacent N-7 guanine forming 1, 2 intrastrand crosslink.[4][5]

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).[9]

Aldehydes such as acrolein and crotonaldehyde found in tobacco smoke or automotive exhaust can form DNA interstrand crosslinks in DNA. Guanine adducts of DNA can also react with protein. A Schiff base formation between protein and aldehyde causes this DNA protein interstrand link

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.
  • Reactive chemicals such as malondialdehyde are formed endogenously as the product of lipid peroxidation. They create etheno adducts formed by aldehyde which undergo rearrangements to form crosslinks on opposite strands.[10]
  • Psoralens are natural compounds (furocoumarins) present in plants. These compounds get activated in the presence of UV - A. They form covalent adducts with pyrimidines. Covalent adducts are formed by linking 3, 4 (pyrone) or 4', 5’ (furan) edge of psoralen to 5, 6 double bond of thymine. Psoralens can form two types of monoadducts and one diadduct (an interstrand crosslink) reacting with thymine.[11] The crosslinking reaction by Psoralens targets TA sequences intercalating in DNA and linking one base of the DNA with the one below it. Psoralen adducts cause replication arrest and are used in the treatment of psoriasis and vitiligo.
  • Formaldehyde (HCHO) induces protein-DNA and protein-protein crosslinks, and is a common reagent of choice for molecular biology experiments.[12] These crosslinks may be reversed by incubation at 70 °C.[13]

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.[14] Once pairing has occurred, the crosslink can be removed and correct information introduced into the damaged chromosome by the process of homologous recombinational repair.

Treatment of E. coli with psoralen-plus-UV light (PUVA) produces interstrand crosslinks in the cells’ DNA. Cole et al.[15] and Sinden and Cole[16] 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.[17] In yeast, three pathways have a role in repair or toleration of crosslinks: homologous recombinational repair, nucleotide excision repair and translesion synthesis.[17]

Recombinational repair of DNA crosslinks also likely occurs in plants where it depends on gene rad51, a recA ortholog. In the plant Arabidopsis thaliana, mutants defective in a gene rad51 paralog XRCC3 are hypersensitive to mitomycin C, a crosslinking agent.[18] In rice (Oryza sativa), mutants with a defective RAD51C gene have increased sensitivity in somatic cells to mitomycin C.[19]

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.[20] 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.[21][22] 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.[21] and Papadaki et al.[22] 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. ^ a b 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. ^ a b 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. ^ Ali-Osman F, Rairkar A, Young P (January 1995). "Formation and repair of 1,3-bis-(2-chloroethyl)-1-nitrosourea and cisplatin induced total genomic DNA interstrand crosslinks in human glioma cells". Cancer Biochem. Biophys. 14 (4): 231–41. PMID 7767897.
  9. ^ 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.
  10. ^ Mathews & Vanholde, Biochemistry, 2nd Edition. Benjamin Cummings Publication
  11. ^ 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).
  12. ^ Formaldehyde Crosslinking Experiments
  13. ^ Niranjanakumaria S, Lasdaa E, Brazasa R, Garcia-Blanco MA (Feb 2002). "Reversible cross-linking combined with immunoprecipitation to study RNA–protein interactions in vivo". Methods. 26 (2): 182–90. doi:10.1016/S1046-2023(02)00021-X. PMID 12054895.
  14. ^ 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
  15. ^ 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.
  16. ^ 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.
  17. ^ a b 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.
  18. ^ Bleuyard JY, White CI (2004). "The Arabidopsis homologue of Xrcc3 plays an essential role in meiosis". EMBO J. 23 (2): 439–49. doi:10.1038/sj.emboj.7600055. PMC 1271761. PMID 14726957.
  19. ^ Kou Y, Chang Y, Li X, Xiao J, Wang S (2012). "The rice RAD51C gene is required for the meiosis of both female and male gametocytes and the DNA repair of somatic cells". J. Exp. Bot. 63 (14): 5323–35. doi:10.1093/jxb/ers190. PMC 3431001. PMID 22859673.
  20. ^ 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.
  21. ^ 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.
  22. ^ 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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