Mechanical evolution of DNA double-strand breaks in the nucleosome

摘要

Author summary Cancer therapy involves generation of damage to DNA by various means, ranging from chemicals to ionizing radiation. The most lethal form of damage is the breaking of the DNA molecule, especially effective when the rupture occurs simultaneously on both sides of the DNA double helix, in what is called a double-strand break (DSB). However, the fracture of the DNA backbone cannot be complete until the whole chemical bonds holding together the two strands are cleaved. This can occur even much later than the action of the chemical or radiation damage. By using sophisticated computer simulations at the molecular scale, we studied the evolution of the initial breaking in the nucleosome—the constitutive building block of chromatin and chromosomes. We show that the initial breaking event follows a complex path, before eventually arriving at the complete fracture of DNA; the energy barrier for separating the DNA from the protein core of the nucleosome are not very high, in the range of a few kBT. The internal mechanical stress is a key parameter, often underappreciated, in determining whether the DNA in the nucleosome will open up, and thus become accessible to the action of nuclear proteins, or it will rather remain deeply hidden in the chromatin and difficult to repair.