Histone Protein Catalyzed Chemistry of Damaged DNA in Nucleosomes
DNA lesions are biologically deleterious because they can adversely affect DNA replication and transcription. Little attention has been paid to the possibility that lesions may react within the biopolymer to produce in more deleterious forms of damage. Furthermore, most studies have been carried out on naked DNA. We recently reported that histone proteins in nucleosome core particles catalyze the cleavage of alkali labile lesions, such abasic sites (AP). The histone proteins accelerate strand scission as much as 450-fold. Abasic site reactivity was investigated using organic synthesis, kinetics, mass spectrometry, and site-specific mutagenesis.
The lysine rich amino terminal tails of the histone proteins, which are often modified post-translationally in cells are primarily responsible for catalyzing strand scission. Histone mediated cleavage of an oxidized abasic lesion produced by several antitumor agents that damage DNA results in modification of the lysine rich tail. This modification raises new questions concerning the possibility that the post-translational modification may affect the histone proteins’ interaction with proteins involved in genetic regulation. These investigations provide insight into the chemical basis of drug action.
For relevant publications see:
• Rapid DNA-Protein Cross-linking and Strand Scission by an Abasic Site in a Nucleosome Core Particle. Sczepanski, J. T.; Wong, R. S.; McKnight, J. N.; Bowman, G. D.; Greenberg, M. M. Proc. Natl. Acad. Sci. USA 2010, 107, 22475-22480.
• Histone Catalyzed Cleavage of Nucleosomal DNA Containing 2-Deoxyribonolactone. Zhou, C.; Greenberg, M. M. J. Am. Chem. Soc. 2012, 134, 8090-8093. “Spotlighted” in the J. Am. Chem. Soc. 2012, 134, 9031.
• Mechanistic Studies on Histone Catalyzed Cleavage of Apyrimidinic/Apurinic Sites in Nucleosome Core Particles. Zhou, C.; Sczepanski, J. T.; Greenberg, M. M. J. Am. Chem. Soc. 2012, 134, 16734-16741.
• Nucleosome Core Particle Catalyzed Strand Scission at Abasic Sites. Sczepanski, J. T.; Zhou, C.; Greenberg, M. M. Biochemistry 2013, 52, 2157-2164.
• Histone Modification via Rapid Cleavage of C4′-Oxidized Abasic Sites in Nucleosome Core Particles. Zhou, C.; Sczepanski, J. T.; Greenberg, M. M. J. Am. Chem. Soc. 2013, 135, 5274-5277. “Spotlighted” in the J. Am. Chem. Soc. 2013, 135, 5933.
• Probing Interactions Between Histone Tails and Nucleosomal DNA via Product and Kinetic Analysis. Weng, L.; Zhou, C.; Greenberg, M. M. ACS Chem. Biol. 2015, 10, 622-630. “Spotlighted” in Chem. Res. Toxicol. 2015, 28, 3. (PMC: 4336632)