title: Activation of DNA damage response signaling by condensed chromatin.
abstract: The DNA damage response (DDR) occurs in the context of chromatin, and architectural features of chromatin have been implicated in DNA damage signaling and repair. Whereas a role of chromatin decondensation in the DDR is well established, we show here that chromatin condensation is integral to DDR signaling. We find that, in response to DNA damage chromatin regions transiently expand before undergoing extensive compaction. Using a protein-chromatin-tethering system to create defined chromatin domains, we show that interference with chromatin condensation results in failure to fully activate DDR. Conversely, forced induction of local chromatin condensation promotes ataxia telangiectasia mutated (ATM)- and ATR-dependent activation of upstream DDR signaling in a break-independent manner. Whereas persistent chromatin compaction enhanced upstream DDR signaling from irradiation-induced breaks, it reduced recovery and survival after damage. Our results demonstrate that chromatin condensation is sufficient for activation of DDR signaling and is an integral part of physiological DDR signaling.
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Burgess
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Program in Cell, Molecular and Developmental Biology, Sackler School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
authors.forename: Bharat
authors.initials: B
authors.lastname: Burman
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kruhlak
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: mistelit@mail.nih.gov.
authors.forename: Tom
authors.initials: T
authors.lastname: Misteli
mesh_terms: D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002843:Chromatin / Q000502:physiology*; D042002:Chromatin Assembly and Disassembly; D004249:DNA Damage; D004260:DNA Repair; D004789:Enzyme Activation; D006801:Humans; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D002843:Chromatin; D011494:Protein Kinases