Journal
DNA REPAIR
Volume 9, Issue 12, Pages 1219-1228Publisher
ELSEVIER
DOI: 10.1016/j.dnarep.2010.09.010
Keywords
DNA damage response; DNA double-strand breaks; Ionizing Radiation-Induced Foci; Ubiquitin; Phosphorylation; DNA repair
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Funding
- Novo Nordisk Foundation
- Danish Medical Research Council
- Danish Cancer Society
- Lundbeck Foundation
- Lundbeck Foundation [R34-2009-3790] Funding Source: researchfish
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DNA double-strand breaks (DSBs) are among the most cytotoxic types of DNA damage, which if left unrepaired can lead to mutations or gross chromosomal aberrations, and promote the onset of diseases associated with genomic instability such as cancer. One of the most discernible hallmarks of the cellular response to DSBs is the accumulation and local concentration of a plethora of DNA damage signaling and repair proteins in the vicinity of the lesion, initiated by ATM-mediated phosphorylation of H2AX (gamma-H2AX) and culminating in the generation of distinct nuclear compartments, so-called Ionizing Radiation-Induced Foci (IRIF). The assembly of proteins at the DSB-flanking chromatin occurs in a highly ordered and strictly hierarchical fashion. To a large extent, this is achieved by regulation of protein-protein interactions triggered by a variety of post-translational modifications including phosphorylation, ubiquitylation, SUMOylation, and acetylation. Over the last decade, insight into the identity of proteins residing in IRIF and the molecular underpinnings of their retention at these structures has been vastly expanded. Despite such advances, however, our understanding of the biological relevance of such DNA repair foci still remains limited. In this review, we focus on recent discoveries on the mechanisms that govern the formation of IRIF, and discuss the implications of such Findings in light of our understanding of the physiological importance of these structures. (C) 2010 Elsevier B.V. All rights reserved.
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