Abstract
Genomic integrity is most threatened by double-strand breaks, which, if left unrepaired, lead to carcinogenesis or cell death. The cell generates a network of protein-protein signaling interactions that emanate from the DNA damage which are now recognized as a rich basis for anti-cancer therapy development. Deciphering the structures of signaling proteins has been an uphill task owing to their large size and complex domain organization. Recent advances in mammalian protein expression/purification and cryo-EM-based structure determination have led to significant progress in our understanding of these large multidomain proteins. This review is an overview of the structural principles that underlie some of the key signaling proteins that function at the double-strand break site. We also discuss some plausible ideas that could be considered for future structural approaches to visualize and build a more complete understanding of protein dynamics at the break site.
Keywords:
DNA damage signaling; mediators; phosphorylation; sensors; ubiquitylation.
© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Acid Anhydride Hydrolases / chemistry
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Acid Anhydride Hydrolases / metabolism
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Animals
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Ataxia Telangiectasia Mutated Proteins / chemistry
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Ataxia Telangiectasia Mutated Proteins / metabolism
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Cell Cycle Proteins / chemistry
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Cell Cycle Proteins / metabolism
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DNA Breaks, Double-Stranded*
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DNA Damage / genetics
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DNA Repair / genetics*
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / metabolism
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Humans
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MRE11 Homologue Protein / chemistry
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MRE11 Homologue Protein / metabolism
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Nuclear Proteins / chemistry
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Nuclear Proteins / metabolism
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Protein Processing, Post-Translational / genetics
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Signal Transduction / genetics*
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Tumor Suppressor Proteins / chemistry
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor p53-Binding Protein 1 / chemistry
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Tumor Suppressor p53-Binding Protein 1 / metabolism
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Ubiquitin-Protein Ligases / chemistry
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Ubiquitin-Protein Ligases / metabolism
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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NBN protein, human
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Nuclear Proteins
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Tumor Suppressor Proteins
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Tumor Suppressor p53-Binding Protein 1
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BARD1 protein, human
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BRAP protein, human
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Ubiquitin-Protein Ligases
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Ataxia Telangiectasia Mutated Proteins
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MRE11 Homologue Protein
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Acid Anhydride Hydrolases
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RAD50 protein, human