Marc Greenberg, the Vernon K. Krieble Professor of Chemistry at Johns Hopkins University (and NYU Chemistry alumnus), will deliver a seminar entitled, "DNA Damage is Only the Beginning." Hosted by Bobby Arora.
For more information about Marc Greenberg, click here.
Abstract: DNA damage is detrimental to genome integrity and can be mutagenic and/or cytotoxic. Frequently, scientists focus on the initially formed damage. Our research group has discovered that the formation of damaged DNA is only the beginning. For instance, damaged DNA can inactivate repair enzymes. In addition, the stability and reactivity of damaged DNA differs from when it is present in free DNA versus within a nucleosome core particle, the monomeric component of chromatin. In some instances, the histone proteins react with the modified DNA producing more biologically deleterious forms of damage. These investigations are often carried out using the reductionist approach of chemistry, in which we generate a single damage site ("lesion") within DNA. This approach simplifies elucidating lesion reactivity. Using this approach, we discovered that certain forms of DNA damage inactivate repair enzymes, such as DNA polymerase b, l and q. These discoveries provide insight into the chemical bases of drugs that kill cells by producing these forms of DNA damage. Our results show that it is not just that some agents damage DNA, but they do so in a manner that challenges the cells' repair systems. Studies within nucleosomal DNA have revealed that histone proteins catalyze strand scission at a variety of abasic sites. In some instances, the histone proteins themselves become modified. Whether the DNA damage induced histone modifications affect genetic expression is a question that we are currently investigating. Alkylated DNA reactivity is also altered within nucleosomes. For instance, we recently reported that the major product of DNA methylating agents, N7-methyl-2'-deoxyguanosine (MdG) undergoes hydrolysis to form abasic sites more slowly in a nucleosome core particle. We also discovered that MdG forms cross-links with histone proteins. DNA-protein cross-links are a very deleterious form of damage. Overall, using chemistry to study damaged DNA facilitates elucidating these biologically important, complex processes and the discovery of previously unrecognized pathways.
(1) Guan, L., and Greenberg, M. M. (2010) Irreversible inhibition of DNA polymerase b by an oxidized abasic lesion, J. Am. Chem. Soc. 132, 5004-5005.
(2) Sczepanski, J. T., Wong, R. S., McKnight, J. N., Bowman, G. D., and Greenberg, M. M. (2010) Rapid DNAprotein cross-linking and strand scission by an abasic site in a nucleosome core particle, Proc. Natl. Acad. Sci. U. S. A. 107, 22475-22480.
(3) Zhou, C., Sczepanski, J. T., and Greenberg, M. M. (2013) Histone modification via rapid cleavage of C4'- oxidized abasic sites in nucleosome core particles, J. Am. Chem. Soc. 135, 5274-5277.
(4) Weng, L., and Greenberg, M. M. (2015) Rapid histone-catalyzed DNA lesion excision and accompanying protein modification in nucleosomes and nucleosome core particles, J. Am. Chem. Soc. 137, 11022-11031.
(5) Yang, K., Park, D., Tretyakova, N. Y., and Greenberg, M. M. (2018) Histone tails decrease N7-methyl-2ʹdeoxyguanosine depurination and yield DNA–protein cross-links in nucleosome core particles and cells, Proc. Natl. Acad. Sci. USA 115, E11212-E11220.
(6) Yang, K., and Greenberg, M. M. (2019) Histone tail sequences balance their role in genetic regulation and the need to protect DNA against destruction in nucleosome core particles containing abasic sites, ChemBioChem 20, 78-82.