Nucleosomal embedding reshapes the dynamics of abasic sites

• Published in: Scientific reports 2020-10, Vol.10 (1), p.17314, Article 17314
• Main Authors: Bignon, Emmanuelle, Claerbout, Victor E. P., Jiang, Tao, Morell, Christophe, Gillet, Natacha, Dumont, Elise
• Format: Article
• Language: English
• Subjects: 631/45/147; 631/92/610; 639/638/563; Animals; Chemical Sciences; DNA; DNA Damage; DNA Repair; DNA-(Apurinic or Apyrimidinic Site) Lyase; Histones; Humanities and Social Sciences; Humans; Molecular Dynamics Simulation; multidisciplinary; Nucleic Acid Conformation; Nucleosomes; or physical chemistry; Science; Science (multidisciplinary); Theoretical and
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-73997-y

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.