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Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining

Non-homologous end joining (NHEJ) is one of the two principal damage repair pathways for DNA double-strand breaks in cells. In this review, we give a brief overview of the system including a discussion of the effects of deregulation of NHEJ components in carcinogenesis and resistance to cancer thera...

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Detalles Bibliográficos
Autores principales: Kefala Stavridi, Antonia, Appleby, Robert, Liang, Shikang, Blundell, Tom L., Chaplin, Amanda K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588668/
https://www.ncbi.nlm.nih.gov/pubmed/32579168
http://dx.doi.org/10.1042/EBC20190092
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author Kefala Stavridi, Antonia
Appleby, Robert
Liang, Shikang
Blundell, Tom L.
Chaplin, Amanda K.
author_facet Kefala Stavridi, Antonia
Appleby, Robert
Liang, Shikang
Blundell, Tom L.
Chaplin, Amanda K.
author_sort Kefala Stavridi, Antonia
collection PubMed
description Non-homologous end joining (NHEJ) is one of the two principal damage repair pathways for DNA double-strand breaks in cells. In this review, we give a brief overview of the system including a discussion of the effects of deregulation of NHEJ components in carcinogenesis and resistance to cancer therapy. We then discuss the relevance of targeting NHEJ components pharmacologically as a potential cancer therapy and review previous approaches to orthosteric regulation of NHEJ factors. Given the limited success of previous investigations to develop inhibitors against individual components, we give a brief discussion of the recent advances in computational and structural biology that allow us to explore different targets, with a particular focus on modulating protein–protein interaction interfaces. We illustrate this discussion with three examples showcasing some current approaches to developing protein–protein interaction inhibitors to modulate the assembly of NHEJ multiprotein complexes in space and time.
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spelling pubmed-75886682020-10-30 Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining Kefala Stavridi, Antonia Appleby, Robert Liang, Shikang Blundell, Tom L. Chaplin, Amanda K. Essays Biochem Cancer Non-homologous end joining (NHEJ) is one of the two principal damage repair pathways for DNA double-strand breaks in cells. In this review, we give a brief overview of the system including a discussion of the effects of deregulation of NHEJ components in carcinogenesis and resistance to cancer therapy. We then discuss the relevance of targeting NHEJ components pharmacologically as a potential cancer therapy and review previous approaches to orthosteric regulation of NHEJ factors. Given the limited success of previous investigations to develop inhibitors against individual components, we give a brief discussion of the recent advances in computational and structural biology that allow us to explore different targets, with a particular focus on modulating protein–protein interaction interfaces. We illustrate this discussion with three examples showcasing some current approaches to developing protein–protein interaction inhibitors to modulate the assembly of NHEJ multiprotein complexes in space and time. Portland Press Ltd. 2020-10 2020-06-24 /pmc/articles/PMC7588668/ /pubmed/32579168 http://dx.doi.org/10.1042/EBC20190092 Text en © 2020 The Author(s). https://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
spellingShingle Cancer
Kefala Stavridi, Antonia
Appleby, Robert
Liang, Shikang
Blundell, Tom L.
Chaplin, Amanda K.
Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining
title Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining
title_full Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining
title_fullStr Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining
title_full_unstemmed Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining
title_short Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining
title_sort druggable binding sites in the multicomponent assemblies that characterise dna double-strand-break repair through non-homologous end joining
topic Cancer
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588668/
https://www.ncbi.nlm.nih.gov/pubmed/32579168
http://dx.doi.org/10.1042/EBC20190092
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