Natalia Tretyakova, Ph.D.
University of Minnesota
NIEHS grantees discovered that monofunctional alkylating agents can form cross-links between DNA and histone proteins, a toxic form of DNA damage. Monofunctional alkylating agents are found in certain environmental pollutants as well as anticancer drugs, such as temozolomide.
The researchers studied the effect of monofunctional alkylating agents in free DNA and in nucleosome core particles, which serve as the protein-containing packaging material for DNA. They found that these chemicals can methylate DNA, forming N7-methyl-2′-deoxyguanosine (MdG). MdG has long been considered a benign lesion because of its minimal effects on DNA structure. However, this study showed that MdG is much more reactive in nucleosome core particles and forms unexpected cross-links with lysine residues in histone proteins. These 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. They also observed the change in nucleosome core particles treated with the alkylating agent methyl methanesulfonate. According to the authors, most studies on MdG have been carried out in free DNA, so the discovery that MdG reactivity differs significantly in nucleosome core particles could have significant implications in how DNA alkylating agents play a role in cell toxicity.
Citation: Yang K, Park D, Tretyakova NY, Greenberg MM. Histone tails decrease N7-methyl-2'-deoxyguanosine depurination and yield DNA-protein cross-links in nucleosome core particles and cells. Proc Natl Acad Sci U S A 115(48):E11212–E11220.