Histone degradation in response to DNA damage enhances chromatin dynamics and recombination rates

Abstract

Nucleosomes are essential for proper chromatin organization and the maintenance of genome integrity. Histones are post-translationally modified and often evicted at sites of DNA breaks, facilitating the recruitment of repair factors. Whether such chromatin changes are localized or genome-wide is debated. Here we show that cellular levels of histones drop 20-40% in response to DNA damage. This histone loss occurs from chromatin, is proteasome-mediated and requires both the DNA damage checkpoint and the INO80 nucleosome remodeler. We confirmed reductions in histone levels by stable isotope labeling of amino acids in cell culture (SILAC)-based mass spectrometry, genome-wide nucleosome mapping and fluorescence microscopy. Chromatin decompaction and increased fiber flexibility accompanied histone degradation, both in response to DNA damage and after artificial reduction of histone levels. As a result, recombination rates and DNA-repair focus turnover were enhanced. Thus, we propose that a generalized reduction in nucleosome occupancy is an integral part of the DNA damage response in yeast that provides mechanisms for enhanced chromatin mobility and homology search.

The Absence of the Arabidopsis Chaperone Complex CAF-1 Produces Mitotic Chromosome Abnormalities and Changes in the Expression Profiles of Genes Involved in DNA Repair

“…Specifically, the increase in somatic HR produced in fas1-4 would be mainly due to high levels of DSBs derived from stalled DNA replication forks (Gao et al, 2012). Alternatively, it has been proposed that histone loss enhances chromatin dynamics and recombination rates (Hauer et al, 2017). …”

Keep moving and stay in a good shape to find your homologous recombination partner

“…First, a checkpoint-mediated disruption of centromeres anchoring has recently been proposed to participate in this DSB-induced chromatin mobility (Strecker et al 2016). Second, a change in chromatin stiffness caused by both local and global chromatin remodelling may account for increased motion (Hauer et al 2017). The increase of DSB ends mobility also depends on the recombination proteins Rad51, Rad54, and has thereby been proposed to promote recombination by allowing efficient scanning of the genome to find the appropriate template for repair Miné-Hattab and Rothstein 2012).…”

The Importance of Satellite Sequence Repression for Genome Stability

“…On one hand, nucleosomes are thought to be an obstacle for the DNA damage repair machinery and thus must be removed. Indeed, following UV damage ubiquitination-mediated histone mobilization has been reported (Wang et al 2006;Lan et al 2012;Adam et al 2013) and in the case of DNA double-strand breaks (DSBs) in yeast, histone ChIP experiments showed a local depletion around an induced DSB (van Attikum et al 2004Attikum et al , 2007, as well as a global loss of histones at high levels of Zeocin-or γIR-induced DNA damage (Hauer et al 2017). Local histone release was shown to depend on the activity of nucleosome remodelers BRG1/RSC and/ or INO80 (van Attikum et al 2004(van Attikum et al , 2007Zhao et al 2009;Jiang et al 2010).…”