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      A conserved SUMO pathway repairs topoisomerase DNA-protein cross-links by engaging ubiquitin-mediated proteasomal degradation

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          Abstract

          A conserved SUMO-ubiquitin-proteasome pathway protects cells from DNA damage induced by topoisomerases.

          Abstract

          Topoisomerases form transient covalent DNA cleavage complexes to perform their reactions. Topoisomerase I cleavage complexes (TOP1ccs) are trapped by camptothecin and TOP2ccs by etoposide. Proteolysis of the trapped topoisomerase DNA-protein cross-links (TOP-DPCs) is a key step for some pathways to repair these lesions. We describe a pathway that features a prominent role of the small ubiquitin-like modifier (SUMO) modification for both TOP1- and TOP2-DPC repair. Both undergo rapid and sequential SUMO-2/3 and SUMO-1 modifications in human cells. The SUMO ligase PIAS4 is required for these modifications. RNF4, a SUMO-targeted ubiquitin ligase (STUbL), then ubiquitylates the TOP-DPCs for their subsequent degradation by the proteasome. This pathway is conserved in yeast with Siz1 and Slx5-Slx8, the orthologs of human PIAS4 and RNF4.

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          The DNA-damage response in human biology and disease.

          Stephen P. Jackson, Jiri Bartek (2009)
          The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.
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            Structure and Function of the 26S Proteasome.

            Jared A.M. Bard, Ellen Goodall, Eric R. Greene … (2018)
            As the endpoint for the ubiquitin-proteasome system, the 26S proteasome is the principal proteolytic machine responsible for regulated protein degradation in eukaryotic cells. The proteasome's cellular functions range from general protein homeostasis and stress response to the control of vital processes such as cell division and signal transduction. To reliably process all the proteins presented to it in the complex cellular environment, the proteasome must combine high promiscuity with exceptional substrate selectivity. Recent structural and biochemical studies have shed new light on the many steps involved in proteasomal substrate processing, including recognition, deubiquitination, and ATP-driven translocation and unfolding. In addition, these studies revealed a complex conformational landscape that ensures proper substrate selection before the proteasome commits to processive degradation. These advances in our understanding of the proteasome's intricate machinery set the stage for future studies on how the proteasome functions as a major regulator of the eukaryotic proteome.
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              Regulation of DNA damage responses by ubiquitin and SUMO.

              Stephen P. Jackson, Daniel Durocher (2013)
              Ubiquitylation and sumoylation, the covalent attachment of the polypeptides ubiquitin and SUMO, respectively, to target proteins, are pervasive mechanisms for controlling cellular functions. Here, we summarize the key steps and enzymes involved in ubiquitin and SUMO conjugation and provide an overview of how they are crucial for maintaining genome stability. Specifically, we review research that has revealed how ubiquitylation and sumoylation regulate and coordinate various pathways of DNA damage recognition, signaling, and repair at the biochemical, cellular, and whole-organism levels. In addition to providing key insights into the control and importance of DNA repair and associated processes, such work has established paradigms for regulatory control that are likely to extend to other cellular processes and that may provide opportunities for better understanding and treatment of human disease. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Sci Adv
                Journal ID (iso-abbrev): Sci Adv
                Journal ID (publisher-id): SciAdv
                Journal ID (hwp): advances
                Title: Science Advances
                Publisher: American Association for the Advancement of Science
                ISSN (Electronic): 2375-2548
                Publication date Collection: November 2020
                Publication date (Electronic): 13 November 2020
                Volume: 6
                Issue: 46
                Electronic Location Identifier: eaba6290
                Affiliations
                [1 ]Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
                [2 ]Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Rockford, IL 61107, USA.
                [3 ]Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
                [4 ]Advanced Imaging and Microscopy Resource, National Institute of Biomedical Imaging and Bioengineering, NIH, MD 20892, USA.
                Author notes
                [* ]Corresponding author. Email: yilun.sun@ 123456nih.gov (Y.S.); jlnitiss@ 123456uic.edu (J.L.N.); pommier@ 123456nih.gov (Y.P.)
                Author information
                http://orcid.org/0000-0002-6249-2704
                http://orcid.org/0000-0003-1245-1338
                http://orcid.org/0000-0002-3548-5090
                http://orcid.org/0000-0002-1013-4972
                http://orcid.org/0000-0002-3108-0758
                Article
                Publisher ID: aba6290
                DOI: 10.1126/sciadv.aba6290
                PMC ID: 7673754
                PubMed ID: 33188014
                SO-VID: 3a1eb0d8-2fd4-440c-a086-501a67e6fe32
                Copyright © Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                Date received : 09 July 2020
                Date accepted : 24 September 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Categories
                Subject: Research Article
                Subject: Research Articles
                Subject: SciAdv r-articles
                Subject: Cancer
                Subject: Molecular Biology
                Subject: Molecular Biology
                Custom metadata
                Copyeditor Kyle Solis

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