Mechanical evolution of DNA double-strand breaks in the nucleosome

PLoS Comput Biol. 2018 Jun 14;14(6):e1006224. doi: 10.1371/journal.pcbi.1006224. eCollection 2018 Jun.

Abstract

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 nucleosomal 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Nucleus / metabolism
  • Computer Simulation
  • DNA
  • DNA Breaks, Double-Stranded*
  • DNA Damage / physiology*
  • DNA Repair / physiology
  • Histones / chemistry
  • Hydrogen Bonding
  • Molecular Dynamics Simulation
  • Nucleosomes / physiology*

Substances

  • Histones
  • Nucleosomes
  • DNA

Associated data

  • figshare/10.6084/m9.figshare.5840706

Grants and funding

This work was funded by SIRIC OncoLille under project ”ModCel” for 2015 and 2016 and a three-year doctoral grant to FL co-funded by the President of Lille-I University and the Government of the Region Nord-Pas de Calais (now Hauts-de-France). Computer resources were provided by the CINES and IDRIS CNRS French Supercomputing Centers under grants a0020707225 and x2016/077225. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.