title: Probing Enhanced Double-Strand Break Formation at Abasic Sites within Clustered Lesions in Nucleosome Core Particles.
abstract: DNA is rapidly cleaved under mild alkaline conditions at apyrimidinic/apurinic sites, but the half-life is several weeks in phosphate buffer (pH 7.5). However, abasic sites are ∼100-fold more reactive within nucleosome core particles (NCPs). Histone proteins catalyze the strand scission, and at superhelical location 1.5, the histone H4 tail is largely responsible for the accelerated cleavage. The rate constant for strand scission at an abasic site is enhanced further in a nucleosome core particle when it is part of a bistranded lesion containing a proximal strand break. Cleavage of this form results in a highly deleterious double-strand break. This acceleration is dependent upon the position of the abasic lesion in the NCP and its structure. The enhancement in cleavage rate at an apurinic/apyrimidinic site rapidly drops off as the distance between the strand break and abasic site increases and is negligible once the two forms of damage are separated by 7 bp. However, the enhancement of the rate of double-strand break formation increases when the size of the gap is increased from one to two nucleotides. In contrast, the cleavage rate enhancement at 2-deoxyribonolactone within bistranded lesions is more modest, and it is similar in free DNA and nucleosome core particles. We postulate that the enhanced rate of double-strand break formation at bistranded lesions containing apurinic/apyrimidinic sites within nucleosome core particles is a general phenomenon and is due to increased DNA flexibility.
authors.affiliation: Department of Chemistry, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Samya
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Chemistry, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Supratim
authors.initials: S
authors.lastname: Chakraborty
authors.affiliation: Department of Chemistry, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Marco Paolo
authors.initials: MP
authors.lastname: Jacinto
authors.affiliation: Department of Chemistry, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Paul
authors.affiliation: Department of Chemistry, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Morgan V
authors.initials: MV
authors.lastname: Balster
authors.affiliation: Department of Chemistry, Johns Hopkins University , Baltimore, Maryland 21218, United States.
authors.forename: Marc M
authors.identifier: http://orcid.org/0000-0002-5786-6118
authors.initials: MM
authors.lastname: Greenberg
mesh_terms: D001080:Apurinic Acid / Q000737:chemistry* / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004277:DNA, Single-Stranded; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009707:Nucleosomes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains
chemical_list: D004277:DNA, Single-Stranded; D006657:Histones; D009707:Nucleosomes; D001080:Apurinic Acid; D004247:DNA