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Marc Greenberg

Professor at the Department of Chemistry, Johns Hopkins University

Mar 16, 2023 à 10:30 AM


André Collet


Natacha Gillet

Sometimes DNA Damage is Only the Beginning

DNA damage is detrimental to genome integrity and can be mutagenic and/or cytotoxic. The latter lies at the etiology of disease but is also the goal of many anti-cancer therapeutics. Consequently understanding this diverse and important group of processes is of paramount importance.

Frequently, scientists focus on the initially formed damage. To understand the consequences of DNA damage and its formation, our group begins its investigations by using the reductionist approach of organic chemistry. Generating a single damage site ("lesion") within DNA simplifies studies on DNA damage and facilitates a deeper understanding. Using this strategy, our research group has discovered that in some instances the formation of damaged DNA is only the beginning.

For instance, some forms of damaged DNA inactivate repair enzymes. These discoveries provide insight into the chemical bases of drugs that kill cells by producing these forms of DNA damage and inspiration for designing inhibitors of such enzymes. Other DNA lesions react with the histone proteins within nucleosome core particles to produce more biologically deleterious forms of damage. Some of these processes that have been discovered in the test tube have been shown to occur in cells.

Overall, combining organic chemistry, biochemistry and cell biology to study damaged DNA facilitates elucidating these biologically important and complex processes, the discovery of previously unrecognized pathways, and the inspiration for designing molecules with useful biological activity.

Relevant references :

(1) Ren, M.; Greenberg, M. M.; Zhou, C. Participation of Histones in DNA Damage and Repair within Nucleosome Core Particles: Mechanism and Applications. Acc. Chem. Res. 2022, 55, 1059-1073.

(2) Jacinto, M. P.; Fried, S. D.; Greenberg, M. M. Intracellular Formation of a DNA Damage-Induced, Histone Post-Translational Modification Following Bleomycin Treatment. J. Am. Chem. Soc. 2022, 144, 7600-7605.

(3) Yuhas, S. C.; Laverty, D. J.; Lee, H.; Majumdar, A.; Greenberg, M. M. Selective Inhibition of DNA Polymerase b by a Covalent Inhibitor. J. Am. Chem. Soc. 2021, 143, 8099-8107.

(4) Yuhas, S. C.; Mishra, A.; DeWeese, T. L.; Greenberg, M. M. Suppression of DNA Polymerase b Activity Is Synthetically Lethal in BRCA1-Deficient Cells. ACS Chem. Biol. 2021, 16, 1339-1343.

(5) Yang, K.; Park, D.; Tretyakova, N. Y.; Greenberg, M. M. Histone Tails Decrease N7-Methyl-2- Deoxyguanosine Depurination and Yield DNA–Protein Cross-Links in Nucleosome Core Particles and Cells. Proc. Natl. Acad. Sci. USA 2018, 115, E11212-E11220.