DNA damage-induced histone loss increases chromatin mobility facilitating repair

Nucleosomes are essential for proper chromatin organization and for maintenance of genome integrity. Histones are post-translationally modified and in some cases evicted at sites of DNA breaks, facilitating recruitment of the repair machinery. Whether such changes are localized or reflect changes in chromatin structure genome-wide is debated. Here we document a genome-wide loss of 20-40% of core histones in response to DNA damage. This loss is attenuated by inhibition of the proteasome and is dependent on the DNA damage checkpoint and the INO80 nucleosome remodeler. Histone loss was confirmed by SILAC-based mass spectroscopy, genome-wide nucleosome mapping and fluoresce microscopy. Live cell imaging combined with super-resolution microscopy shows that histone degradation results in chromatin decompaction and increased flexibility. As direct proof, we find that chromatin expands and moves more flexibly in cells artificially reduced for histones. We further show that histone reduction enhances recombination rates and DNA repair turnover. Thus our findings introduce genome-wide histone loss as a novel and integral part of the DNA damage response, providing a mechanism for enhanced chromatin mobility and homology search.