Key Points
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Post-translational modification of proteins by ubiquitin and ubiquitin-like modifiers (UBLs) including SUMO have crucial and widespread roles in promoting cellular responses to DNA double-strand breaks (DSBs).
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Cascades involving E1 activating enzymes, E2 conjugating enzymes and E3 ligases underlie the conjugation of ubiquitin and UBLs to cellular target proteins. These modifications are recognized and decoded by proteins containing ubiquitin- or UBL-binding domains, and are removed by ubiquitin- or UBL-specific proteases.
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Chromatin ubiquitylation by RNF8, RNF168 and other E3 ubiquitin ligases gives rise to a complex ubiquitylation landscape at DSB sites that promotes accumulation of a range of important DNA repair factors near the lesions. Multiple regulatory mechanisms control and restrain the activity of these ubiquitin-mediated recruitment programmes.
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Two major pathways for DSB repair, non-homologous end joining (NHEJ) and homologous recombination, are used by eukaryotic cells. Ubiquitin-dependent signalling processes have a key role in determining DSB repair pathway choice and functionality through the regulation of factors that control DSB end resection, as well as by modification of key NHEJ and homologous recombination components themselves.
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A further level of complexity in DSB signalling pathways arises from the involvement of SUMO and other UBLs in promoting the functionality of these processes. Crosstalk between and co-regulation by ubiquitin and SUMO occurs at multiple levels within DSB repair responses.
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Dysfunctions in ubiquitin signalling factors involved in DSB repair are tightly linked to severe disorders and syndromes resulting from genomic instability, demonstrating the physiological importance of these ubiquitin-dependent signalling responses. Mechanistic insights into how ubiquitin- and UBL-dependent processes promote DSB repair offer new therapeutic opportunities for diseases resulting from genomic instability.
Abstract
DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions. The swift recognition and faithful repair of such damage is crucial for the maintenance of genomic stability, as well as for cell and organismal fitness. Signalling by ubiquitin, SUMO and other ubiquitin-like modifiers (UBLs) orchestrates and regulates cellular responses to DSBs at multiple levels, often involving extensive crosstalk between these modifications. Recent findings have revealed compelling insights into the complex mechanisms by which ubiquitin and UBLs regulate protein interactions with DSB sites to promote accurate lesion repair and protection of genome integrity in mammalian cells. These advances offer new therapeutic opportunities for diseases linked to genetic instability.
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Acknowledgements
The authors apologize to all researchers whose important findings could not be cited owing to page limitations, and thank Jiri Lukas (The Novo Nordisk Foundation Center for Protein Research) for critical reading of the manuscript. Work in the authors' laboratory is funded by grants from The Novo Nordisk Foundation (Grant no. NNF14CC0001), The European Research Council, The Danish Council for Independent Research, The Lundbeck Foundation and The Danish Cancer Society.
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Glossary
- Writers, readers and erasers
-
Factors that lay down (writers), recognize (readers) and remove (erasers) specific post-translational modifications of proteins.
- Atypical polyubiquitin chains
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Low-abundant ubiquitin chain types, including K6, K27, K29 and K33 linkages, whose cellular functions are not yet well understood.
- RING-type E3 ligases
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A family of E3 ubiquitin ligases containing the RING (really interesting new gene) domain, more than 600 of which are encoded in the human genome, and which mediate direct transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to the substrate protein.
- HECT-type E3 ligase
-
A type of E3 ubiquitin ligase, approximately 30 of which are present in mammals, harbouring a carboxy-terminal HECT (homologous to the E6-AP C terminus) domain that accepts ubiquitin from an E2 enzyme through formation of a thioester intermediate and subsequently transfers the ubiquitin moiety to a protein substrate.
- Translesion DNA synthesis
-
A DNA damage tolerance pathway involving specialized, low-fidelity DNA polymerases that allow replication past DNA lesions, albeit in a potentially error-prone manner that contributes to DNA damage-induced mutagenesis.
- OTU family
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A subfamily of cysteine protease DUBs that contain an ovarian tumour (OTU) domain.
- Ubiquitin-selective segregase p97
-
A highly abundant AAA+ ATPase (also known as VCP (valosin-containing protein)) that remodels ubiquitylated client proteins and complexes and has a widespread involvement in ubiquitin-mediated cellular processes.
- Immunoglobulin class-switch recombination
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(CSR). The process in activated B lymphocytes that promotes the generation of different antibody isotypes with the same antigen specificity by switching antibody heavy-chain gene segments, initiated by programmed DSBs.
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Schwertman, P., Bekker-Jensen, S. & Mailand, N. Regulation of DNA double-strand break repair by ubiquitin and ubiquitin-like modifiers. Nat Rev Mol Cell Biol 17, 379–394 (2016). https://doi.org/10.1038/nrm.2016.58
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DOI: https://doi.org/10.1038/nrm.2016.58
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