Global chromatin compaction limits the strength of the DNA damage response

Abstract

In response to DNA damage, chromatin undergoes a global decondensation process that has been proposed to facilitate genome surveillance. However, the impact that chromatin compaction has on the DNA damage response (DDR) has not directly been tested and thus remains speculative. We apply two independent approaches (one based on murine embryonic stem cells with reduced amounts of the linker histone H1 and the second making use of histone deacetylase inhibitors) to show that the strength of the DDR is amplified in the context of “open” chromatin. H1-depleted cells are hyperresistant to DNA damage and present hypersensitive checkpoints, phenotypes that we show are explained by an increase in the amount of signaling generated at each DNA break. Furthermore, the decrease in H1 leads to a general increase in telomere length, an as of yet unrecognized role for H1 in the regulation of chromosome structure. We propose that slight differences in the epigenetic configuration might account for the cell-to-cell variation in the strength of the DDR observed when groups of cells are challenged with DNA breaks.

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

“…It was proposed that the decondensed chromatin structure of pluripotent mES cells, mainly maintained by enhanced global histone acetylation and reduced histone methylation, as well as abundant chromatin remodeling complexes, contributes to the development of larger γH2AX foci [54] . Further relaxation of ES cell chromatin by lessening the level of the linker histone H1 causes ES cells hyperresistant to DNA damage, as the DDR is enhanced in the context of open chromatin [55] . Although DNA damage induces γH2AX foci in both differentiated and stem cells, the distribution of γH2AX in the nucleus of stem cells is distinct.…”

Higher-order Genome Organization in Human Disease

“…Further evidence for a critical role of chromatin structure in susceptibility to DNA damage and repair comes from analysis of the DNA damage response in embryonic stem cells, which are unique in that they have a strict requirement to maintain their genomes in pristine conditions because any genomic defect will be propagated as the stem cells differentiate into various tissues. ES cells lacking the linker histone H1, one of the key global architectural components of chromatin, are characterized by less compacted chromatin and, remarkably, have a heightened DNA damage response and are able to repair DSB more rapidly after irradiation (Fan et al 2005;Murga et al 2007). This is likely because of the global decondensation of chromatin in these cells since the effect can be mimicked by treatment of cells with the histone-deacetylase inhibitor trichostatin A, which also leads to chromatin decondensation (Murga et al 2007).…”

“…ES cells lacking the linker histone H1, one of the key global architectural components of chromatin, are characterized by less compacted chromatin and, remarkably, have a heightened DNA damage response and are able to repair DSB more rapidly after irradiation (Fan et al 2005;Murga et al 2007). This is likely because of the global decondensation of chromatin in these cells since the effect can be mimicked by treatment of cells with the histone-deacetylase inhibitor trichostatin A, which also leads to chromatin decondensation (Murga et al 2007). These observations suggest that chromatin structure directly affects susceptibility of the genome to damage and that different regions, such as heterochromatin and euchromatin, in the same genome respond differently to DNA damage.…”

Chromosomal Protein HMGN1 Enhances the Heat Shock-induced Remodeling of Hsp70 Chromatin

“…Taken together, the results suggest that the chromatin-modifying activities of HMGN1 optimize chromatin alterations necessary for the orderly progression of DNArelated activities such as transcription or repair. Interestingly, depletion of H1 also leads to alteration in chromatin modifications and impairs the rate of DNA repair (53,54). The emerging picture suggests that chromatin architectural proteins affect the levels of chromatin modifications, thereby participating in epigenetic regulation of gene expression and affecting the cellular phenotype.…”