Global chromatin compaction limits the strength of the DNA damage response.
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.
Murga
Matilde
M
Genomic Instability Group, Molecular Oncology Programme, Spanish National Cancer Center, Madrid 28029, Spain.
Jaco
Isabel
I
Fan
Yuhong
Y
Soria
Rebeca
R
Martinez-Pastor
Barbara
B
Cuadrado
Myriam
M
Yang
Seung-Min
SM
Blasco
Maria A
MA
Skoultchi
Arthur I
AI
Fernandez-Capetillo
Oscar
O
D000818:Animals; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D009153:Mutagens / Q000494:pharmacology; D012854:Sister Chromatid Exchange / Q000187:drug effects; D016615:Telomere / Q000378:metabolism
D002843:Chromatin; D006657:Histones; D006877:Hydroxamic Acids; D009153:Mutagens; C012589:trichostatin A