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Published online
doi:10.1083/jcb.200704140
The Journal of Cell Biology, Vol. 178, No. 7, 1101-1108
The Rockefeller University Press, 0021-9525 $30.00
© Murga et al.
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Report

Global chromatin compaction limits the strength of the DNA damage response



Matilde Murga1, Isabel Jaco2, Yuhong Fan3, Rebeca Soria1, Barbara Martinez-Pastor1, Myriam Cuadrado1, Seung-Min Yang3, Maria A. Blasco2, Arthur I. Skoultchi3, and Oscar Fernandez-Capetillo1

1 Genomic Instability Group and 2 Telomeres and Telomerase Group, Molecular Oncology Programme, Spanish National Cancer Center, Madrid 28029, Spain
3 Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10467

Correspondence to O. Fernandez-Capetillo: ofernandez{at}cnio.es

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.

Y. Fan's present address is the School of Biology and the Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332.

Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; ATR, ATM and Rad3 related; BP1, binding protein 1; Chk1, chaperoning checkpoint kinase 1; CO-FISH, chromosome orientation FISH; DDR, DNA damage response; DSB, double-strand break; ES, embryonic stem; HDAC, histone deacetylase; HR, homologous recombination; HU, hydroxyurea; IR, ionizing radiation; MMS, methyl-methane sulfonate; Q-FISH, quantitative FISH; SMC1, structural maintenance of chromosomes 1; TSA, trichostatin A; T-SCE, telomeric sister chromatid exchange.


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