The complex pattern of methyl groups tagging the DNA molecule is also called a “second code”, because it is an additional level of information along with the genetic information, which is laid down in the sequence of bases in DNA. Methyl tags seal the DNA molecule: Abundantly methylated DNA is silenced and cannot be transcribed. Numerous studies have shown that cancer cells and healthy cells differ in their methylation patterns. It is therefore considered as established that there is a link between DNA methylation and cancer.
Professor Dr. Frank Lyko from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) pursues studies on the effects of methyl tags in cells. In a joint project with Rudolf Jaenisch from the Massachusetts Institute of Technology (MIT) in Boston, he has now shown how blocking methylation affects cancer development.
The researchers studied mice carrying an oncogenic mutation in the K-ras gene that makes it certain for them to develop tumors. They additionally turned off the gene for the Dnmt3 enzyme, which is responsible for adding methyl groups to DNA. “Thus we were able to directly study the effects of methyl tags on carcinogenesis,” Lyko explains.
While control animals with functional Dnmt3a developed small tumors in the lungs, the mice lacking Dnmt3a developed large and rapidly growing lung tumors. The absence of methyl tags apparently promotes tumor growth. The team led by Lyko and Jaenisch have determined, for the first time, the methyl pattern of the complete tumor genomes of both Dnmt3a-positive and Dnmt3a-negative lung tumors using a special sequencing method.
“Methylation seems to act as a protective shield,” says Lyko explaining his results. “The shield can have gaps that promote cancer – this is what we observe in the animals with functional Dnmt3a. However, if it is completely absent, as in the Dnm3a-negative mice, regulation of the activity of numerous genes is defective and the cancer grows even more rapidly.”
A couple of years ago, the scientists had discovered in tumor cells that genes slowing down cancer growth are particularly frequently silenced by methylation. The researchers have therefore been searching for substances to inhibit methylation and, thus, make cancer brakes functional again. “We may have underestimated the complexity of the situation,” Frank Lyko admits. The researchers now conclude: Drugs targeting DNA methylation must become much more precise in order to fight cancer efficiently.
Picture caption: Both strands of this DNA double helix carry methyl tags, illustrated here as glowing bowls.
Günter Raddatz, Qing Gao, Sebastian Bender, Rudolf Jaenisch and Frank Lyko: Dnmt3a protects active chromosome domains against cancer-associated hypomethylation. Plos Genetics 2012, DOI: 10.1371/journal.pgen.1003146
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