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Microarray screening reveals two non-conventional SUMO-binding modules linked to DNA repair by non-homologous end-joining

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Cabello-Lobato, Maria Jose, Jenner, Matthew, Cisneros-Aguirre, Metztli, Brüninghoff, Kira, Sandy, Zac, da Costa, Isabelle C., Jowitt, Thomas A., Loch, Christian M., Jackson, Stephen P., Wu, Qian, Mootz, Henning D., Stark, Jeremy M., Cliff, Matthew J. and Schmidt, Christine K. (2022) Microarray screening reveals two non-conventional SUMO-binding modules linked to DNA repair by non-homologous end-joining. Nucleic Acids Research, 50 (8). pp. 4732-4754. doi:10.1093/nar/gkac237

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Official URL: http://dx.doi.org/10.1093/nar/gkac237

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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.

Item Type: Journal Article
Subjects: Q Science > QH Natural history
Q Science > QP Physiology
R Medicine > RC Internal medicine
Divisions: Faculty of Science, Engineering and Medicine > Science > Chemistry
Library of Congress Subject Headings (LCSH): Cellular signal transduction, Post-translational modification, DNA repair , Small ubiquitin-related modifiers
Journal or Publication Title: Nucleic Acids Research
Publisher: Oxford University Press
ISSN: 0305-1048
Official Date: 6 May 2022
Dates:
DateEvent
6 May 2022Published
14 April 2022Available
25 March 2022Accepted
Volume: 50
Number: 8
Page Range: pp. 4732-4754
DOI: 10.1093/nar/gkac237
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
BB/N019997/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/R01212/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
R01CA256989National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01CA240392National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
C6/A18796Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
DRCPGM\100005Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
GA 268536European Research Councilhttp://dx.doi.org/10.13039/501100000781
C6946/A24843Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
WT203144Wellcome Trusthttp://dx.doi.org/10.13039/100010269
SBF005/1025Wellcome Trusthttp://dx.doi.org/10.13039/100010269
MR/W017865/1][MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
BB/M017982/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268

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