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Mol Cell. 2018 Jan 4;69(1):36-47.e7. doi: 10.1016/j.molcel.2017.11.021. Epub 2017 Dec 14.

Replication Stress Shapes a Protective Chromatin Environment across Fragile Genomic Regions.

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Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
Molecular Cytogenetics Core Facility, National Cancer Institute, NIH, Frederick, MD 21702, USA.
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892, USA. Electronic address:


Recent integrative epigenome analyses highlight the importance of functionally distinct chromatin states for accurate cell function. How these states are established and maintained is a matter of intense investigation. Here, we present evidence for DNA damage as an unexpected means to shape a protective chromatin environment at regions of recurrent replication stress (RS). Upon aberrant fork stalling, DNA damage signaling and concomitant H2AX phosphorylation coordinate the FACT-dependent deposition of macroH2A1.2, a histone variant that promotes DNA repair by homologous recombination (HR). MacroH2A1.2, in turn, facilitates the accumulation of the tumor suppressor and HR effector BRCA1 at replication forks to protect from RS-induced DNA damage. Consequently, replicating primary cells steadily accrue macroH2A1.2 at fragile regions, whereas macroH2A1.2 loss in these cells triggers DNA damage signaling-dependent senescence, a hallmark of RS. Altogether, our findings demonstrate that recurrent DNA damage contributes to the chromatin landscape to ensure the epigenomic integrity of dividing cells.


DNA repair; FACT; chromatin; macro-histone; macroH2A1.2; replication stress; senescence

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