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Disassembly of the Shieldin Complex by TRIP13

In the past decade, the study of the major DNA double strand break (DSB) repair pathways, homologous recombination (HR) and classical non-homologous end joining (C-NHEJ), has revealed a vast and intricate network of regulation.  The choice between HR and C-NHEJ is largely controlled at the step of D...

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Autores principales: Sarangi, Prabha, Clairmont, Connor S., D’Andrea, Alan D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480811/
https://www.ncbi.nlm.nih.gov/pubmed/32420796
http://dx.doi.org/10.1080/15384101.2020.1758435
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author Sarangi, Prabha
Clairmont, Connor S.
D’Andrea, Alan D.
author_facet Sarangi, Prabha
Clairmont, Connor S.
D’Andrea, Alan D.
author_sort Sarangi, Prabha
collection PubMed
description In the past decade, the study of the major DNA double strand break (DSB) repair pathways, homologous recombination (HR) and classical non-homologous end joining (C-NHEJ), has revealed a vast and intricate network of regulation.  The choice between HR and C-NHEJ is largely controlled at the step of DNA end-resection. A pro-C-NHEJ cascade commencing with 53BP1 and culminating in the newly discovered REV7-Shieldin complex impedes end resection and therefore HR. Importantly, loss of any component of this pathway confers PARP inhibitor resistance in BRCA1-deficient cells; hence, their study is of great clinical importance. The newest entrant on the scene of end resection regulation is the ATPase TRIP13 that disables the pro-C-NHEJ cascade by promoting a novel conformational change of the HORMA protein REV7. Here, we tie these new findings and factors with previous research on the regulation of DSB repair and HORMA proteins, and suggest testable hypotheses for how TRIP13 could specifically inactivate REV7-Shieldin to promote HR. We also discuss these biological questions in the context of clinical therapeutics.
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spelling pubmed-74808112020-09-15 Disassembly of the Shieldin Complex by TRIP13 Sarangi, Prabha Clairmont, Connor S. D’Andrea, Alan D. Cell Cycle Review In the past decade, the study of the major DNA double strand break (DSB) repair pathways, homologous recombination (HR) and classical non-homologous end joining (C-NHEJ), has revealed a vast and intricate network of regulation.  The choice between HR and C-NHEJ is largely controlled at the step of DNA end-resection. A pro-C-NHEJ cascade commencing with 53BP1 and culminating in the newly discovered REV7-Shieldin complex impedes end resection and therefore HR. Importantly, loss of any component of this pathway confers PARP inhibitor resistance in BRCA1-deficient cells; hence, their study is of great clinical importance. The newest entrant on the scene of end resection regulation is the ATPase TRIP13 that disables the pro-C-NHEJ cascade by promoting a novel conformational change of the HORMA protein REV7. Here, we tie these new findings and factors with previous research on the regulation of DSB repair and HORMA proteins, and suggest testable hypotheses for how TRIP13 could specifically inactivate REV7-Shieldin to promote HR. We also discuss these biological questions in the context of clinical therapeutics. Taylor & Francis 2020-05-18 /pmc/articles/PMC7480811/ /pubmed/32420796 http://dx.doi.org/10.1080/15384101.2020.1758435 Text en © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Review
Sarangi, Prabha
Clairmont, Connor S.
D’Andrea, Alan D.
Disassembly of the Shieldin Complex by TRIP13
title Disassembly of the Shieldin Complex by TRIP13
title_full Disassembly of the Shieldin Complex by TRIP13
title_fullStr Disassembly of the Shieldin Complex by TRIP13
title_full_unstemmed Disassembly of the Shieldin Complex by TRIP13
title_short Disassembly of the Shieldin Complex by TRIP13
title_sort disassembly of the shieldin complex by trip13
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480811/
https://www.ncbi.nlm.nih.gov/pubmed/32420796
http://dx.doi.org/10.1080/15384101.2020.1758435
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