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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 ISSN 0305-1048.
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Official URL: http://dx.doi.org/10.1093/nar/gkac237
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 | |||||||||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QH Natural history Q Science > QP Physiology R Medicine > RC Internal medicine |
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| 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: |
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| 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 (Creative Commons) | |||||||||||||||||||||||||||||||||||||||
| Date of first compliant deposit: | 22 April 2022 | |||||||||||||||||||||||||||||||||||||||
| Date of first compliant Open Access: | 22 April 2022 | |||||||||||||||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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