Murga Matilde, Jaco Isabel, Fan Yuhong, Soria Rebeca, Martinez-Pastor Barbara, Cuadrado Myriam, Yang Seung-Min, Blasco Maria A, Skoultchi Arthur I, Fernandez-Capetillo Oscar
Genomic Instability Group, Molecular Oncology Programme, Spanish National Cancer Center, Madrid 28029, Spain.
J Cell Biol. 2007 Sep 24;178(7):1101-8. doi: 10.1083/jcb.200704140.
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.
作为对DNA损伤的响应，染色质会经历一个整体的解聚过程，该过程被认为有助于基因组监测。然而，染色质压缩对DNA损伤反应（DDR）的影响尚未得到直接验证，因此仍只是推测。我们采用了两种独立的方法（一种基于连接组蛋白H1含量减少的小鼠胚胎干细胞，另一种使用组蛋白脱乙酰酶抑制剂）来表明，DDR的强度在“开放”染色质的背景下会被放大。H1缺失的细胞对DNA损伤具有高度抗性，并表现出超敏感的检查点，我们表明这些表型可以通过每个DNA断裂处产生的信号量增加来解释。此外，H1的减少导致端粒长度普遍增加，这是H1在染色体结构调控中尚未被认识到的作用。我们提出，表观遗传构型的微小差异可能解释了在细胞群体受到DNA断裂挑战时观察到的DDR强度在细胞间的差异。
