title: Chromatin perturbations during the DNA damage response in higher eukaryotes.
abstract: The DNA damage response is a widely used term that encompasses all signaling initiated at DNA lesions and damaged replication forks as it extends to orchestrate DNA repair, cell cycle checkpoints, cell death and senescence. ATM, an apical DNA damage signaling kinase, is virtually instantaneously activated following the introduction of DNA double-strand breaks (DSBs). The MRE11-RAD50-NBS1 (MRN) complex, which has a catalytic role in DNA repair, and the KAT5 (Tip60) acetyltransferase are required for maximal ATM kinase activation in cells exposed to low doses of ionizing radiation. The sensing of DNA lesions occurs within a highly complex and heterogeneous chromatin environment. Chromatin decondensation and histone eviction at DSBs may be permissive for KAT5 binding to H3K9me3 and H3K36me3, ATM kinase acetylation and activation. Furthermore, chromatin perturbation may be a prerequisite for most DNA repair. Nucleosome disassembly during DNA repair was first reported in the 1970s by Smerdon and colleagues when nucleosome rearrangement was noted during the process of nucleotide excision repair of UV-induced DNA damage in human cells. Recently, the multi-functional protein nucleolin was identified as the relevant histone chaperone required for partial nucleosome disruption at DBSs, the recruitment of repair enzymes and for DNA repair. Notably, ATM kinase is activated by chromatin perturbations induced by a variety of treatments that do not directly cause DSBs, including treatment with histone deacetylase inhibitors. Central to the mechanisms that activate ATR, the second apical DNA damage signaling kinase, outside of a stalled and collapsed replication fork in S-phase, is chromatin decondensation and histone eviction associated with DNA end resection at DSBs. Thus, a stress that is common to both ATM and ATR kinase activation is chromatin perturbations, and we argue that chromatin perturbations are both sufficient and required for induction of the DNA damage response.
authors.affiliation: Departments of Radiation Oncology and Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Hillman Cancer Center, Research Pavilion, Suite 2.6, 5117Centre Avenue, Pittsburgh, PA 15213-1863, USA. Electronic address: bakkenistcj@upmc.edu.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bakkenist
authors.affiliation: Executive Director, Duke Cancer Institute, William W. Shingleton Professor of Pharmacology and Cancer Biology, Duke University School of Medicine, 422 Seeley Mudd Building, Box 3917, Durham, NC 27 710, USA. Electronic address: michael.kastan@duke.edu.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Kastan
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002843:Chromatin / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D056890:Eukaryota / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction
chemical_list: D002843:Chromatin; D004247:DNA; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; ATR; Chromatin perturbations; Double-strand breaks (DSBs); Ionizing radiation (IR); Nucleolin