Exposure to methylating agents, which are used in the lab and in chemotherapy, can cause an unexpected form of DNA damage, a new study reveals. These chemicals can methylate guanosine bases in DNA, forming N7-methyl-2′-deoxyguanosine (MdG). MdG minimally perturbs the DNA structure, so it has long been considered a benign lesion. However, MdG can be hydrolyzed, effectively deleting a base from the DNA strand. Such a mutation can be toxic.
Marc M. Greenberg and Kun Yang of Johns Hopkins University and Natalia Y. Tretyakova and Daeyoon Park of the University of Minnesota Twin Cities studied this effect in free DNA and in nucleosome core particles, the protein-containing packaging material for DNA. MdG hydrolysis in these particles occurs much more slowly than in purified isolated DNA. This means that MdG is less likely to lead to abasic sites in living tissues. But MdG also forms unexpected cross-links with lysine residues in histone proteins in the nucleosome core particles (Proc. Natl. Acad. Sci. U.S.A. 2018, DOI: 10.1073/pnas.1813338115). Such cross-links are extremely toxic because they can block essential DNA functions such as replication and transcription. The researchers observed these cross-links in engineered nucleosome core particles containing MdG at specific sites, in wild-type particles treated with methyl methanesulfonate, and in chromatin isolated from similarly treated cells. The researchers hope that their findings will lead to a reevaluation of the toxicity of chemotherapeutic monofunctional methylating agents, such as temozolomide.