DNA networking

from Wikipedia, the free encyclopedia

The DNA cross-linking refers to the linking of DNA with other molecules . The cross-linked DNA belongs to the DNA adducts , a form of DNA damage .

properties

DNA crosslinking can be triggered, among other things, by crosslinking agents or ionizing radiation . Some crosslinking agents are also fixing agents or alkylating agents . The crosslinking can take place within a DNA strand (intramolecularly) or intermolecularly between two DNA molecules (e.g. in the case of a DNA double helix ) or between DNA and another molecule, e.g. B. with a DNA-binding protein or other molecules. DNA replication is inhibited by cross-linked nucleobases , while DNA repair is triggered. The occasional faulty repair of cross-linked DNA can lead to mutations which, in certain combinations, can lead to cancer . The repair is mainly carried out by nucleotide excision repair (NER), by translational synthesis (TLS) and homologous recombination (HR). Rad51 proteins are involved in repairing cross-linked DNA. Patients with Fanconi anemia are particularly sensitive to DNA cross-linking between two strands of DNA.

Exogenous networking

A DNA link is used in medicine for chemotherapy , because cells that divide rapidly, such as tumor cells, tend to suffer more from DNA damage than cells at rest . Some alkylating agents such as 1,3-bis (2-chloroethyl) -1-nitrosourea (BCNU, carmustine ) and mustard are used because they create intermolecular cross-links at the N7 position of guanines .

Cisplatin (cis-diamminedichloroplatinum (II)) and its derivatives like carboplatin and oxaliplatin form DNA adducts , intramolecular and intermolecular crosslinks.

DNA damage can also be caused by ionizing radiation , e.g. B. ultraviolet light (such as thymine, - dimers after a 2 + 2 cycloaddition ), X-rays or of radionuclides emitted radiation.

In biochemistry, DNA crosslinking is used, among other things, for mutagenesis , for fixation and, after a Southern blot, for fixation on a nitrocellulose or nylon membrane. Crosslinking with formaldehyde can be reversed by heating to 70 ° C, which is why DNA crosslinking with formaldehyde is used to determine protein-DNA interactions .

Endogenous networking

Nitrous acid is absorbed from nitrites in food. Nitrous acid crosslinks DNA at the N2 position of guanines in CG sequences. As a result of the metabolism of nitrites, various nitroso compounds such as nitrosamines are formed .

Reactive compounds such as dialdehydes (e.g. malondialdehyde ) can arise after lipid peroxidation , as a result of which crosslinking ethene adducts are formed.

Aldehydes such as acrolein and crotonaldehyde can form adducts with guanines, which in turn can form Schiff bases with proteins.

Psoralens are found in some plants and can intercalate with DNA . When exposed to UV-A , they form adducts with pyrimidines . The networking with psoralens mainly affects TA sequences. Psoralen adducts produce an arrest of the cell cycle and are used in the therapy of psoriasis and vitiligo .

Web links

  • PDB  1AIO - Interactive structure for cisplatin and DNA adduct formation
  • PDB  204D - Interactive structure for psoralen and crosslinked DNA

Individual evidence

  1. ^ AJ Deans, SC West: DNA interstrand crosslink repair and cancer. In: Nature Reviews Cancer . Volume 11, Number 7, July 2011, ISSN  1474-1768 , pp. 467-480, doi : 10.1038 / nrc3088 , PMID 21701511 , PMC 3560328 (free full text).
  2. ↑ PR Andreassen, K. Ren: Fanconi anemia proteins, DNA interstrand crosslink repair pathways, and cancer therapy. In: Current cancer drug targets. Volume 9, Number 1, February 2009, ISSN  1873-5576 , pp. 101-117. PMID 19200054 .
  3. ↑ AM Gruver, KA Miller, C. Rajesh et al. : The ATPase motif in RAD51D is required for resistance to DNA interstrand crosslinking agents and interaction with RAD51C . In: Mutagenesis . 20, No. 6, November 2005, pp. 433-40. doi : 10.1093 / mutage / gei059 . PMID 16236763 .
  4. ↑ J. Zhang, JC Walter: Mechanism and regulation of incisions during DNA interstrand cross-link repair. In: DNA repair. April 2014, ISSN  1568-7856 , doi : 10.1016 / j.dnarep.2014.03.018 , PMID 24768452 . (electronic publication before printing)
  5. ↑ F. Ali-Osman, A. Rairkar, P. Young: Formation and repair of 1,3-bis- (2-chloroethyl) -1-nitrosourea and cisplatin induced total genomic DNA interstrand crosslinks in human glioma cells . In: Cancer Biochem. Biophys . 14, No. 4, January 1995, pp. 231-41. PMID 7767897 .
  6. ↑ CA Rabik, ME Dolan: Molecular mechanisms of resistance and toxicity associated with platinating agents. In: Cancer treatment reviews. Volume 33, number 1, February 2007, ISSN  0305-7372 , pp. 9-23, doi : 10.1016 / j.ctrv.2006.09.006 , PMID 17084534 , PMC 1855222 (free full text).
  7. ↑ N. Poklar, DS Pilch, SJ Lippard, EA Redding, SU Dunham, KJ Breslauer: Influence of cisplatin intrastrand crosslinking on the conformation, thermal stability, and energetics of a 20-mer DNA duplex . In: Proc. Natl. Acad. Sci. USA . 93, No. 15, July 1996, pp. 7606-11. doi : 10.1073 / pnas.93.15.7606 . PMID 8755522 . PMC 38793 (free full text).
  8. ↑ GN Rudd, JA Hartley, RL Souhami: Persistence of cisplatin-induced DNA interstrand crosslinking in peripheral blood mononuclear cells from elderly and young individuals . In: Cancer Chemother. Pharmacol . 35, No. 4, 1995, pp. 323-6. doi : 10.1007 / BF00689452 . PMID 7828275 .
  9. ^ JT Reardon, A. Sancar: Thermodynamic cooperativity and kinetic proofreading in DNA damage recognition and repair. In: Cell cycle (Georgetown, Tex.). Volume 3, Number 2, February 2004, ISSN  1538-4101 , pp. 141-144, PMID 14712076 .
  10. ↑ S. Niranjanakumari, E. Lasda, R. Brazas, MA Garcia-Blanco: Reversible cross-linking combined with immunoprecipitation to study RNA-protein interactions in vivo. In: Methods (San Diego, Calif.). Volume 26, Number 2, February 2002, pp. 182-190, ISSN  1046-2023 . doi : 10.1016 / S1046-2023 (02) 00021-X . PMID 12054895 .
  11. ↑ J. Kennedy-Darling, LM Smith: Measuring the formaldehyde protein: DNA crosslink reversal rate. In: Analytical chemistry. May 2014, ISSN  1520-6882 , doi : 10.1021 / ac501354y , PMID 24848408 . (electronic publication before printing)
  12. ↑ Christopher K. Mathews, Kensal E. Van Holde, Dean R. Appling: Biochemistry . Edition: Revised. Prentice Hall, Toronto 2012, ISBN 978-0-13-800464-4 .
  13. ^ Q. Wu, LA Christensen, RJ Legerski, KM Vasquez: Mismatch repair participates in error-free processing of DNA interstrand crosslinks in human cells. In: EMBO reports. Volume 6, Number 6, June 2005, ISSN  1469-221X , pp. 551-557, doi : 10.1038 / sj.embor.7400418 , PMID 15891767 , PMC 1369090 (free full text).