CpG dinucleotide

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A CpG dinucleotide is a chemical combination of two nucleotides that have the nucleobases cytosine and guanine . Occasionally, other names are used, such as CG -stelle , CG-Ort , CpG- Motiv and the like. Ä. In English, CpG site and CpG dinucleotide are common.

In general, the term “CpG dinucleotide” refers to a location within the genetic make-up ( DNA ) that contains deoxycytidine - phosphoric acid - deoxyguanosine (in the 5'-3 ' direction). Due to the complementary base pairing at such a point, which is also called the CpG site , two dinucleotides occur in the DNA double strand at each point.

The CpG sites play a special role in the genomes of some living things (e.g. in mammals) because they are the subject of DNA methylation there and have a special frequency and distribution. The CpG sites or dinucleotides should not be confused with the CpG islands . CpG islands are defined areas where CpG sites are more abundant than other sections of the underlying genome .

composition

Schematic representation of a CpG dinucleotide as a section of a double-stranded DNA molecule (dsDNA). The actual CpG dinucleotide (5'-deoxycytidine-phosphoric acid-deoxyguanosine-3 ') on the indicated strand (“Watson”) is shown in black. The base pairing to the complementary strand ("crick") is shown in gray. The alignment (5'-3 '), numbering and transitions to parts not shown (wavy lines) of the dsDNA molecule are also shown in gray. The blue marking of the named parts (cytosine-phosphate-guanine) results in the writing "CpG".

Within double-stranded DNA, CpG is a sequence that is exactly the same on the complementary strand in the 5 '- 3' direction: 

 5' ... pNpNpNpCpGpNpNpN  ... 3'
         | | | | | | | |
 3' ...  NpNpNpGpCpNpNpNp ... 5'

        (N: beliebige Nukleinbase)

The chemical composition of a DNA-internal CpG motif is shown schematically opposite.

Distribution of the CpG motif

Since four nucleobases ( A , C , G and T ) are represented in the DNA, there are 4 * 4 = 16 different two-base sequence motifs (ApA, ApC, ..., CpG, ..., GpC, .. ., TpG, TpT). The CpG motif differs from the other 15 two- base motifs in that it has a different distribution and biological function in the double-stranded DNA of various living things, including humans, than the other two-base motifs. The CpG motif occurs there statistically in CpG islands and can be methylated in different ways. The DNA methylation resulting from cytosine to 5-methylcytosine (guanosine is not methylated). The degree of methylation of CpG sites, especially in the CpG islands, affects gene regulation and other epigenetic properties. The methylation of CpG sites plays a crucial role in cancer research and treatment, as it is often disturbed in tumors.

The low statistical frequency of CG sequences is due to CG suppression .

Methyl CpG binding proteins

Methyl-CpG-binding domain protein 1 ( Mbd1 ) binds to methylated CpG dinucleotides, as does Kaiso , the Kaiso-like proteins and SRA domain proteins .

Therapeutic uses

Adjuvant effect in vaccines

In bacteria , CpG sites often do not have the same distribution, methylation and importance as in humans . These differences in foreign DNA are recognized by the innate immune defense of humans (and that of other vertebrates ) and some immune cells are activated. The intracellular pattern recognition receptor TLR-9 plays the decisive role here . This property of the unmethylated CpG motifs can be exploited to achieve an adjuvant effect in the organism. It can be produced synthetically, nukleasestabile CpG oligonucleotides as adjuvant ( adjuvant ) in clinical studies for the therapy of tumor diseases (including cancer vaccines ), infectious diseases and allergies tested. The stability against nucleases is achieved by a phosphorothioate modification in which an oxygen atom of the phosphate residue is replaced by a sulfur atom.

Gene therapy

In bacterial plasmids for gene therapy , the CpG dinucleotides are partially removed in order to avoid premature degradation of the plasmid.

Individual evidence

  1. ↑ a b M. Gardiner-Garden, M. Frommer: CpG islands in vertebrate genomes. In: Journal of molecular biology. Volume 196, Number 2, July 1987, pp. 261-282, PMID 3656447 .
  2. ↑ R. Chatterjee, C. Vinson: CpG methylation recruits sequence specific transcription factors essential for tissue specific gene expression. In: Biochimica et Biophysica Acta . Volume 1819, number 7, July 2012, pp. 763-770, doi : 10.1016 / j.bbagrm.2012.02.014 , PMID 22387149 , PMC 3371161 (free full text).
  3. ↑ E. Scarano, M. Iaccarino, P. Grippo, E. Parisi: The heterogeneity of thymine methyl group origin in DNA pyrimidine isostichs of developing sea urchin embryos. In: Proceedings of the National Academy of Sciences . Volume 57, Number 5, May 1967, pp. 1394-1400, PMID 5231746 , PMC 224485 (free full text).
  4. ↑ K. Jabbari, G. Bernardi: Cytosine methylation and CpG, TpG (CpA) and TpA frequencies. In: Genes. Volume 333, May 2004, pp. 143-149, doi : 10.1016 / j.gene.2004.02.043 , PMID 15177689 .
  5. ↑ Z. Zhao, L. Han: CpG islands: algorithms and applications in methylation studies. In: Biochemical and biophysical research communications. Volume 382, ​​number 4, May 2009, pp. 643-645, doi : 10.1016 / j.bbrc.2009.03.076 , PMID 19302978 , PMC 2679166 (free full text).
  6. ↑ AM Deaton, A. Bird: CpG islands and the regulation of transcription. In: Genes & development. Volume 25, number 10, May 2011, pp. 1010-1022, doi : 10.1101 / gad.2037511 , PMID 21576262 , PMC 3093116 (free full text).
  7. ^ JA Law, SE Jacobsen: Establishing, maintaining and modifying DNA methylation patterns in plants and animals. In: Nature Reviews Genetics . Volume 11, number 3, March 2010, pp. 204–220, doi : 10.1038 / nrg2719 , PMID 20142834 , PMC 3034103 (free full text).
  8. ↑ D. Sproul, RR Meehan: Genomic insights into cancer-associated aberrant CpG island hypermethylation. In: Briefings in functional genomics. Volume 12, number 3, May 2013, pp. 174–190, doi : 10.1093 / bfgp / els063 , PMID 23341493 , PMC 3662888 (free full text).
  9. ↑ L. Li, BF Chen, WY Chan: An epigenetic regulator: methyl-CpG-binding domain protein 1 (MBD1). In: International journal of molecular sciences. Volume 16, number 3, 2015, pp. 5125–5140, doi : 10.3390 / ijms16035125 , PMID 25751725 , PMC 4394467 (free full text).
  10. ^ PA Defossez, I. Stancheva: Biological functions of methyl-CpG-binding proteins. In: Progress in molecular biology and translational science. Volume 101, 2011, pp. 377-398, doi : 10.1016 / B978-0-12-387685-0.00012-3 , PMID 21507359 .
  11. ↑ ZG Ramirez-Ortiz, CA Specht, JP Wang, CK Lee, DC Bartholomeu, RT Gazzinelli, SM Levitz: Toll-like receptor 9-dependent immune activation by unmethylated CpG motifs in Aspergillus fumigatus DNA. In: Infection and Immunity. Volume 76, number 5, May 2008, pp. 2123-2129, doi : 10.1128 / IAI.00047-08 , PMID 18332208 , PMC 2346696 (free full text).
  12. ↑ H. Shirota, D. Tross, DM Klinman: CpG Oligonucleotides as Cancer Vaccine Adjuvants. In: Vaccines. Volume 3, number 2, 2015, pp. 390-407, doi : 10.3390 / vaccines3020390 , PMID 26343193 , PMC 4494345 (free full text).
  13. ↑ S. Rotenfußer include: CpG oligonucleotides: Immunotherapy after the pattern of bacterial DNA. In: Deutsches Ärzteblatt 98, 2001, pp. A981-A985.
  14. ^ Y. Takahashi, M. Nishikawa, Y. Takakura: Development of safe and effective nonviral gene therapy by eliminating CpG motifs from plasmid DNA vector. In: Frontiers in bioscience (Scholar edition). Volume 4, 2012, pp. 133-141, PMID 22202048 .