DNA double-strand breaks in heterochromatin elicit fast repair protein recruitment, histone H2AX phosphorylation and relocation to euchromatin
Burkhard Jakob,Jörn Splinter,Sandro Conrad,Kay-Obbe Voss,Daniele Zink,Marco Durante,Markus Löbrich,Gisela Taucher-Scholz +7 more
TLDR
This work demonstrates that H2AX is early phosphorylated within HC, but the damage site is subsequently expelled from the center to the periphery of chromocenters within ∼20 min, and describes a local decondensation of HC at the sites of ion hits, potentially allowing for DSB movement via physical forces.Abstract:
DNA double-strand breaks (DSBs) can induce chromosomal aberrations and carcinogenesis and their correct repair is crucial for genetic stability. The cellular response to DSBs depends on damage signaling including the phosphorylation of the histone H2AX (γH2AX). However, a lack of γH2AX formation in heterochromatin (HC) is generally observed after DNA damage induction. Here, we examine γH2AX and repair protein foci along linear ion tracks traversing heterochromatic regions in human or murine cells and find the DSBs and damage signal streaks bending around highly compacted DNA. Given the linear particle path, such bending indicates a relocation of damage from the initial induction site to the periphery of HC. Real-time imaging of the repair protein GFP-XRCC1 confirms fast recruitment to heterochromatic lesions inside murine chromocenters. Using single-ion microirradiation to induce localized DSBs directly within chromocenters, we demonstrate that H2AX is early phosphorylated within HC, but the damage site is subsequently expelled from the center to the periphery of chromocenters within ∼20 min. While this process can occur in the absence of ATM kinase, the repair of DSBs bordering HC requires the protein. Finally, we describe a local decondensation of HC at the sites of ion hits, potentially allowing for DSB movement via physical forces.read more
Citations
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Chromatin Remodeling at DNA Double-Strand Breaks
TL;DR: Early chromatin-based events that promote the formation of open, relaxed chromatin structures at DSBs and that allow the DNA-repair machinery to access the spatially confined region surrounding the DSB are reviewed, thereby facilitating mammalian DSB repair.
Journal ArticleDOI
Biological Consequences of Radiation-induced DNA Damage: Relevance to Radiotherapy
TL;DR: The concepts developed rely in part on the fact that ionising radiation creates significant levels of clustered DNA damage, including complex double-strand breaks (DSB), to kill tumour cells as clustered damage sites are difficult to repair.
Journal ArticleDOI
Ten principles of heterochromatin formation and function.
TL;DR: In this paper, the authors discuss conserved principles of heterochromatin formation and function using selected examples from studies of a range of eukaryotes, from yeast to human, with an emphasis on insights obtained from unicellular model organisms.
Journal ArticleDOI
Opportunities and challenges of radiotherapy for treating cancer
Dörthe Schaue,William H. McBride +1 more
TL;DR: This Review focuses on how mechanistic processes might be targeted to improve the outcome of radiotherapy at the individual patient level, and would seem a more productive avenue of treatment than simply trying to increase the radiation dose delivered to the tumour.
Journal ArticleDOI
Prime, repair, restore: the active role of chromatin in the DNA damage response.
TL;DR: This work revisits the existing access-repair-restore model and proposes a new working model involving priming chromatin for repair and restoration as a concerted process, and discusses how this impacts on both genomic and epigenomic stability and plasticity.
References
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DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139
TL;DR: In this paper, a histone H2AX species that has been phosphorylated specifically at serine 139 was found to be a major component of DNA double-stranded break.
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DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
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ATM Phosphorylates Histone H2AX in Response to DNA Double-strand Breaks
TL;DR: The results clearly establish ATM as the major kinase involved in the phosphorylation of H2AX and suggest that ATM is one of the earliest kinases to be activated in the cellular response to double-strand breaks.
Journal ArticleDOI
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Arkady Celeste,Simone Petersen,Peter J. Romanienko,Oscar Fernandez-Capetillo,Hua Tang Chen,Olga A. Sedelnikova,Bernardo Reina-San-Martin,Vincenzo Coppola,Eric Meffre,Michael J. Difilippantonio,Christophe E. Redon,Duane R. Pilch,Alexandru Olaru,Michael Eckhaus,R. Daniel Camerini-Otero,Lino Tessarollo,Ferenc Livak,Katia Manova,William M. Bonner,Michel C. Nussenzweig,André Nussenzweig +20 more
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