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

Autor:	Cabello-Lobato MJ; Manchester Cancer Research Centre (MCRC), Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 555 Wilmslow Road, Manchester M20 4GJ, UK., Jenner M; Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.; Warwick Integrative Synthetic Biology (WISB) Centre, University of Warwick, Coventry CV4 7AL, UK., Cisneros-Aguirre M; Department of Cancer Genetics and Epigenetics, Irell and Manella Graduate School of Biological Sciences Beckman Research Institute of the City of Hope, 1500 E Duarte Rd, Duarte, CA 91010, USA., Brüninghoff K; Institute of Biochemistry, University of Muenster, Corrensstraße 36, 48149 Muenster, Germany., Sandy Z; Manchester Cancer Research Centre (MCRC), Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 555 Wilmslow Road, Manchester M20 4GJ, UK., da Costa IC; Manchester Cancer Research Centre (MCRC), Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 555 Wilmslow Road, Manchester M20 4GJ, UK., Jowitt TA; Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK., Loch CM; AVM Biomed, Pottstown, PA19464, USA., Jackson SP; Wellcome/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK., Wu Q; Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK., Mootz HD; Institute of Biochemistry, University of Muenster, Corrensstraße 36, 48149 Muenster, Germany., Stark JM; Department of Cancer Genetics and Epigenetics, Irell and Manella Graduate School of Biological Sciences Beckman Research Institute of the City of Hope, 1500 E Duarte Rd, Duarte, CA 91010, USA., Cliff MJ; Manchester Institute of Biotechnology (MIB) and School of Chemistry, University of Manchester, Manchester M1 7DN, UK., Schmidt CK; Manchester Cancer Research Centre (MCRC), Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 555 Wilmslow Road, Manchester M20 4GJ, UK.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2022 May 06; Vol. 50 (8), pp. 4732-4754.
DOI:	10.1093/nar/gkac237
Abstrakt:	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. (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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