Histone Tail Sequences Balance Their Role in Genetic Regulation and the Need To Protect DNA against Destruction in Nucleosome Core Particles Containing Abasic Sites

Abstract

Abasic sites (AP) are produced 10,000 times in a single cell per day. Strand cleavage at AP is accelerated ~100-fold within a nucleosome core particle (NCP) compared to free DNA. The lysine (Lys) rich N-terminal tails of histone proteins catalyze single strand break formation via a mechanism utilized by base excision repair enzymes, despite the general dearth of Glu, Asp, and His amino acids that are typically responsible for deprotonation of Schiff base intermediates. Incorporating Glu, Asp, or His proximal to Lys residues in histone N-terminal tails increases AP reactivity as much as ~6-fold. The rate acceleration is due to more facile DNA cleavage of Schiff base intermediates. These observations raise the possibility that histone proteins may have evolved to minimize the presence of His, Glu, and Asp in their Lys rich N-terminal tails to guard against enhancing the toxic effects of DNA damage.

Histones participate in base excision repair of 8-oxodGuo by transiently cross-linking with active repair intermediates in nucleosome core particles

“…More strikingly, in addition to forming DPCs, histone tails promoted both the β-elimination of 3′-phosphate from hOGG1-AP DPC and the release of hOGG1 from hOGG1-PUA DPC (Figure 3E ). The former role is probably attributable to the basic environment provided by the N-terminal tails of histones ( 28 ); that is, histones acted as general acid/base catalysts ( 24 , 29 ). The latter role involved trapping of 3′-PUA by histones, thus preventing retrograde reaction of hOGG1 with the active intermediate.…”

DNA–Protein Cross-Link Formation in Nucleosome Core Particles Treated with Methyl Methanesulfonate

“…Reversible histone DPCs are formed with MdG and AP in NCPs (Scheme ). DPC MdG is distinguishable from DPC AP by exploiting their differences in sensitivity to alkaline conditions. ,,− The DNA within DPC AP is cleaved over time by the lysine residues within the proximal N-terminal histone tails. − Complete strand scission at the cross-linked AP sites is achieved upon treatment with NaOH (0.1 M, 37 °C, 30 min). The DNA within a DPC MdG is uncleaved under these conditions.…”

In vitro eradication of abasic site-mediated DNA–peptide/protein cross-links by Escherichia coli long-patch base excision repair

“…An AP site is one of the most abundant endogenous DNA lesions ( 2 ). It acts as an electrophile that can react with protein nucleophiles ( e.g., lysine and cysteine residues) to yield various types of covalent DPCs including Schiff base ( 16 , 17 , 18 , 22 , 24 , 25 , 45 , 46 ), thiazolidine ( 47 , 48 , 49 , 50 ), S -glycosidic ( 51 ), and N -glycosidic ( 52 , 53 ) bond-linked AP-protein adducts. These DPCs are either new types of DNA lesions or proposed to temporarily protect the lesions from the error-prone repair ( 17 , 49 ).…”