Shieldin - the protector of DNA ends.
TLDR
The identification of shieldin and the various models of Shieldin action are summarized and some outstanding questions requiring answers are highlighted to gain a full molecular understanding of shieldIn function.Abstract:
DNA double‐strand breaks are a threat to genome integrity and cell viability. The nucleolytic processing of broken DNA ends plays a central role in dictating the repair processes that will mend these lesions. Usually, DNA end resection promotes repair by homologous recombination, whereas minimally processed ends are repaired by non‐homologous end joining. Important in this process is the chromatin‐binding protein 53BP1, which inhibits DNA end resection. How 53BP1 shields DNA ends from nucleases has been an enduring mystery. The recent discovery of shieldin, a four‐subunit protein complex with single‐stranded DNA‐binding activity, illuminated a strong candidate for the ultimate effector of 53BP1‐dependent end protection. Shieldin consists of REV7, a known 53BP1‐pathway component, and three hitherto uncharacterized proteins: C20orf196 (SHLD1), FAM35A (SHLD2), and CTC‐534A2.2 (SHLD3). Shieldin promotes many 53BP1‐associated activities, such as the protection of DNA ends, non‐homologous end joining, and immunoglobulin class switching. This review summarizes the identification of shieldin and the various models of shieldin action and highlights some outstanding questions requiring answers to gain a full molecular understanding of shieldin function.read more
Citations
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Journal ArticleDOI
Phase separation of 53BP1 determines liquid-like behavior of DNA repair compartments.
Sinan Kilic,Aleksandra Lezaja,Marco Gatti,Eliana Bianco,Jone Michelena,Ralph Imhof,Matthias Altmeyer +6 more
TL;DR: It is suggested that 53BP1 phase separation integrates localized DNA damage recognition and repair factor assembly with global p53‐dependent gene activation and cell fate decisions.
Journal ArticleDOI
A Genetic Map of the Response to DNA Damage in Human Cells
Michele Olivieri,Michele Olivieri,Tiffany Cho,Tiffany Cho,Alejandro Álvarez-Quilón,Kejiao Li,Matthew J. Schellenberg,Michal Zimmermann,Nicole Hustedt,Silvia Emma Rossi,Salomé Adam,Henrique Melo,Anne Margriet Heijink,Guillermo Sastre-Moreno,Nathalie Moatti,Rachel K. Szilard,Andrea McEwan,Alexanda K. Ling,Almudena Serrano-Benitez,Tajinder Ubhi,Sumin Feng,Judy Pawling,Irene Delgado-Sainz,Michael W. Ferguson,James W. Dennis,James W. Dennis,Grant W. Brown,Felipe Cortés-Ledesma,R. Scott Williams,Alberto Martin,Dongyi Xu,Daniel Durocher,Daniel Durocher +32 more
TL;DR: A map of the DNA damage response provides a rich resource to study this fundamental cellular system and has implications for the development and use of genotoxic agents in cancer therapy.
Journal ArticleDOI
The molecular basis and disease relevance of non-homologous DNA end joining
TL;DR: This Review first discusses repair pathway choice between NHEJ and other DSB repair pathways, then integrates recent insights into the mechanisms of N HEJ synapsis with updates on other steps of NheJ, such as DNA end processing and ligation.
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DNA damage kinase signaling: checkpoint and repair at 30 years.
TL;DR: The current understanding of DNA damage signaling kinases is reviewed, delineating the key substrates in budding yeast and humans and discussing the major substrate regulatory mechanisms involved in checkpoint responses and DNA repair.
Journal ArticleDOI
Stabilization of chromatin topology safeguards genome integrity
Fena Ochs,Gopal Karemore,Gopal Karemore,Ezequiel Miron,Ezequiel Miron,Jill M. Brown,Hana Sedlackova,Maj-Britt Rask,Marko Lampe,Veronica J. Buckle,Lothar Schermelleh,Jiri Lukas,Claudia Lukas +12 more
TL;DR: Super-resolution microscopy is used to show that 53BP1 and RIF1 form an autonomous functional module that stabilizes three-dimensional chromatin topology at sites of DNA breakage, and proposes that, besides providing a structural scaffold to protect DNA ends against aberrant processing, 53BP 1 and Rif1 safeguard epigenetic integrity at loci that are disrupted by DNA breakages.
References
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Journal ArticleDOI
53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks
Samuel F. Bunting,Elsa Callen,Nancy Wong,Hua Tang Chen,Federica Polato,Amanda Gunn,Anne Bothmer,Niklas Feldhahn,Oscar Fernandez-Capetillo,Liu Cao,Xiaoling Xu,Chu-Xia Deng,Toren Finkel,Michel C. Nussenzweig,Michel C. Nussenzweig,Jeremy M. Stark,André Nussenzweig +16 more
TL;DR: It is shown that DNA breaks in Brca1-deficient cells are aberrantly joined into complex chromosome rearrangements by a process dependent on the nonhomologous end-joining (NHEJ) factors 53BP1 and DNA ligase 4, illustrating that HR and NHEJ compete to process DNA breaks that arise during DNA replication.
Journal ArticleDOI
Playing the End Game: DNA Double-Strand Break Repair Pathway Choice
TL;DR: Recent insights are reviewed into the mechanisms that influence the choice between competing DSB repair pathways, how this is regulated during the cell cycle, and how imbalances in this equilibrium result in genome instability.
Journal ArticleDOI
Double-Strand Break End Resection and Repair Pathway Choice
TL;DR: The components of the end resection machinery, the role of end structure, and the cell-cycle phase on resection and the interplay of end processing with NHEJ are reviewed.
Journal ArticleDOI
Human CtIP promotes DNA end resection
Alessandro A. Sartori,Claudia Lukas,Julia Coates,Martin Mistrik,Shuang Fu,Jiri Bartek,Richard Baer,Jiri Lukas,Stephen P. Jackson +8 more
TL;DR: These findings establish evolutionarily conserved roles for CtIP-like proteins in controlling DSB resection, checkpoint signalling and homologous recombination.
Journal ArticleDOI
Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends.
TL;DR: Monitoring 5'-strand resection at inducible DSB ends in yeast and identified proteins required for two stages of resection shows that the Mre11-Rad50-Xrs2 complex (MRX) initiates 5' degradation, whereas Sgs1 and Dna2 degrade 5' strands exposing long 3' strands.
Related Papers (5)
53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks
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Guotai Xu,J. Ross Chapman,Inger Brandsma,Jingsong Yuan,Martin Mistrik,Peter Bouwman,Jirina Bartkova,Ewa Gogola,Daniël O. Warmerdam,Marco Barazas,Janneke E. Jaspers,Kenji Watanabe,Mark Pieterse,Ariena Kersbergen,Wendy Sol,Patrick H.N. Celie,Philip C. Schouten,Bram van den Broek,Ahmed Salman,Marja Nieuwland,Iris de Rink,Jorma J. de Ronde,Kees Jalink,Simon J. Boulton,Junjie Chen,Dik C. van Gent,Jiri Bartek,Jos Jonkers,Piet Borst,Sven Rottenberg,Sven Rottenberg +30 more