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Nucleosomal embedding reshapes the dynamics of abasic sites

Abstract : Apurinic/apyrimidinic (AP) sites are the most common DNA lesions, which benefit from a most efficient repair by the base excision pathway. The impact of losing a nucleobase on the conformation and dynamics of B-DNA is well characterized. Yet AP sites seem to present an entirely different chemistry in nucleosomal DNA, with lifetimes reduced up to 100-fold, and the much increased formation of covalent DNA-protein cross-links leading to strand breaks, refractory to repair. We report microsecond range, all-atom molecular dynamics simulations that capture the conformational dynamics of AP sites and their tetrahydrofuran analogs at two symmetrical positions within a nucleosome core particle, starting from a recent crystal structure. Different behaviours between the deoxyribo-based and tetrahydrofuran-type abasic sites are evidenced. The two solvent-exposed lesion sites present contrasted extrahelicities, revealing the crucial role of the position of a defect around the histone core. Our all-atom simulations also identify and quantify the frequency of several spontaneous, non-covalent interactions between AP and positively-charged residues from the histones H2A and H2B tails that prefigure DNA-protein cross-links. Such an in silico mapping of DNA-protein cross-links gives important insights for further experimental studies involving mutagenesis and truncation of histone tails to unravel mechanisms of DPCs formation.
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https://hal.archives-ouvertes.fr/hal-03157466
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Submitted on : Friday, November 12, 2021 - 12:28:17 PM
Last modification on : Sunday, June 26, 2022 - 3:19:04 AM
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Emmanuelle Bignon, Victor Claerbout, Tao Jiang, Christophe Morell, Natacha Gillet, et al.. Nucleosomal embedding reshapes the dynamics of abasic sites. Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.17314. ⟨10.1038/s41598-020-73997-y⟩. ⟨hal-03157466⟩

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