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Published online
doi:10.1083/jcb.200612031
The Journal of Cell Biology, Vol. 178, No. 2, 209-218
The Rockefeller University Press, 0021-9525 $30.00
© Kim et al.
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Article

Heterochromatin is refractory to {gamma}-H2AX modification in yeast and mammals



Jung-Ae Kim1,2, Michael Kruhlak3, Farokh Dotiwala1,2, André Nussenzweig3, and James E. Haber1,2

1 Rosenstiel Center and 2 Department of Biology, Brandeis University, Waltham, MA 02454
3 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Correspondence to James E. Haber: haber{at}brandeis.edu

Double-strand break (DSB) damage in yeast and mammalian cells induces the rapid ATM (ataxia telangiectasia mutated)/ATR (ataxia telangiectasia and Rad3 related)-dependent phosphorylation of histone H2AX ({gamma}-H2AX). In budding yeast, a single endonuclease-induced DSB triggers {gamma}-H2AX modification of 50 kb on either side of the DSB. The extent of {gamma}-H2AX spreading does not depend on the chromosomal sequences. DNA resection after DSB formation causes the slow, progressive loss of {gamma}-H2AX from single-stranded DNA and, after several hours, the Mec1 (ATR)-dependent spreading of {gamma}-H2AX to more distant regions. Heterochromatic sequences are only weakly modified upon insertion of a 3-kb silent HMR locus into a {gamma}-H2AX–covered region. The presence of heterochromatin does not stop the phosphorylation of chromatin more distant from the DSB. In mouse embryo fibroblasts, {gamma}-H2AX distribution shows that {gamma}-H2AX foci increase in size as chromatin becomes more accessible. In yeast, we see a high level of constitutive {gamma}-H2AX in telomere regions in the absence of any exogenous DNA damage, suggesting that yeast chromosome ends are transiently detected as DSBs.

Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; CPY, carboxy peptidase Y; DSB, double-strand break; MMS, methylmethanesulfonate; NCS, neocarzinostatin; TPE, telomere position effect; TSA, trichostatin A.


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