Mechanical evolution of DNA double-strand breaks in the nucleosome

Fabrizio Cleri (1, 2) , Fabio Landuzzi (1, 2) , Ralf Blossey (3)

1 IEMN - Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520
2 PHYSIQUE - IEMN - Physique - IEMN
3 UGSF - Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576

Double strand breaks (DSB) in the DNA backbone are the most lethal type of defect induced in the cell nucleus by chemical and radiation treatments of cancer. However, little is known about the outcomes of damage in nucleoso-mal DNA, and on its effects on damage repair. We performed microsecond-long molecular dynamics computer simulations of nucleosomes including a DSB at various sites, to characterize the early stages of the evolution of this DNA lesion. The damaged structures are studied by the essential dynamics of DNA and histones, and compared to the intact nucleosome, thus exposing key features of the interactions. All DSB configurations tend to remain compact, with only the terminal bases interacting with histone proteins. Umbrella sampling calculations show that broken DNA ends at the DSB must overcome a free-energy barrier to detach from the nucleosome core. Finally, by calculating the covariant mechanical stress, we demonstrate that the coupled bending and torsional stress can force the DSB free ends to open up straight, thus making it accessible to damage signalling proteins.

Domaines: Bio-Informatique, Biologie Systémique [q-bio.QM]

Fabrizio Cleri, Fabio Landuzzi, Ralf Blossey. Mechanical evolution of DNA double-strand breaks in the nucleosome. PLoS Computational Biology, 2018, ⟨10.1371/journal.pcbi.1006224⟩. ⟨hal-02341200⟩