Microarray screening reveals two non-conventional SUMO-binding modules linked to DNA repair by non-homologous end-joining.
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Authors
Cabello-Lobato, Maria Jose
Cisneros-Aguirre, Metztli
Brüninghoff, Kira
Sandy, Zac
da Costa, Isabelle C
Jowitt, Thomas A
Loch, Christian M
Mootz, Henning D
Cliff, Matthew J
Publication Date
2022-05-06Journal Title
Nucleic Acids Res
ISSN
0305-1048
Publisher
Oxford University Press (OUP)
Volume
50
Issue
8
Pages
4732-4754
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Cabello-Lobato, M. J., Jenner, M., Cisneros-Aguirre, M., Brüninghoff, K., Sandy, Z., da Costa, I. C., Jowitt, T. A., et al. (2022). Microarray screening reveals two non-conventional SUMO-binding modules linked to DNA repair by non-homologous end-joining.. Nucleic Acids Res, 50 (8), 4732-4754. https://doi.org/10.1093/nar/gkac237
Description
Funder: British Heart Foundation
Abstract
SUMOylation is critical for numerous cellular signalling pathways, including the maintenance of genome integrity via the repair of DNA double-strand breaks (DSBs). If misrepaired, DSBs can lead to cancer, neurodegeneration, immunodeficiency and premature ageing. Using systematic human proteome microarray screening combined with widely applicable carbene footprinting, genetic code expansion and high-resolution structural profiling, we define two non-conventional and topology-selective SUMO2-binding regions on XRCC4, a DNA repair protein important for DSB repair by non-homologous end-joining (NHEJ). Mechanistically, the interaction of SUMO2 and XRCC4 is incompatible with XRCC4 binding to three other proteins important for NHEJ-mediated DSB repair. These findings are consistent with SUMO2 forming a redundant NHEJ layer with the potential to regulate different NHEJ complexes at distinct levels including, but not limited to, XRCC4 interactions with XLF, LIG4 and IFFO1. Regulation of NHEJ is not only relevant for carcinogenesis, but also for the design of precision anti-cancer medicines and the optimisation of CRISPR/Cas9-based gene editing. In addition to providing molecular insights into NHEJ, this work uncovers a conserved SUMO-binding module and provides a rich resource on direct SUMO binders exploitable towards uncovering SUMOylation pathways in a wide array of cellular processes.
Keywords
Humans, DNA Repair Enzymes, DNA Repair, Protein Binding, DNA Breaks, Double-Stranded, DNA End-Joining Repair
Sponsorship
European Research Council (268536)
Cancer Research UK (18796)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)
Wellcome Trust (206388/Z/17/Z)
Identifiers
35420136, PMC9071424
External DOI: https://doi.org/10.1093/nar/gkac237
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337171
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