Assembly and function of DNA double-strand break repair foci in mammalian cells

TY - JOUR

T1 - Assembly and function of DNA double-strand break repair foci in mammalian cells

AU - Bekker-Jensen, Simon

AU - Mailand, Niels

N1 - Copyright © 2010 Elsevier B.V. All rights reserved.

PY - 2010/12/10

Y1 - 2010/12/10

N2 - 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 (γ-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.

AB - 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 (γ-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.

KW - Animals

KW - BRCA1 Protein

KW - Cell Nucleus

KW - Chromatin

KW - DNA Breaks, Double-Stranded

KW - DNA Repair

KW - DNA-Binding Proteins

KW - Genomic Instability

KW - Guanine Nucleotide Exchange Factors

KW - Histones

KW - Humans

KW - Intracellular Signaling Peptides and Proteins

KW - Multiprotein Complexes

KW - Nuclear Proteins

KW - Phosphorylation

KW - Protein Processing, Post-Translational

KW - Trans-Activators

KW - Ubiquitin-Protein Ligases

KW - Ubiquitination

U2 - 10.1016/j.dnarep.2010.09.010

DO - 10.1016/j.dnarep.2010.09.010

M3 - Journal article

C2 - 21035408

SN - 1568-7864

VL - 9

SP - 1219

EP - 1228

JO - DNA Repair

JF - DNA Repair

IS - 12

ER -