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

Authors
  • Kefala Stavridi, Antonia1
  • Appleby, Robert1
  • Liang, Shikang1
  • Blundell, Tom L1
  • Chaplin, Amanda K1
  • 1 Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB21GA, Cambridgeshire, U.K.
Type
Published Article
Journal
Essays in biochemistry
Publication Date
Oct 26, 2020
Volume
64
Issue
5
Pages
791–806
Identifiers
DOI: 10.1042/EBC20190092
PMID: 32579168
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. © 2020 The Author(s).

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