Concerted SUMO-targeted ubiquitin ligase activities of TOPORS and RNF4 are essential for stress management and cell proliferation.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
22 Apr 2024
22 Apr 2024
Historique:
received:
05
05
2023
accepted:
26
03
2024
medline:
23
4
2024
pubmed:
23
4
2024
entrez:
22
4
2024
Statut:
aheadofprint
Résumé
Protein SUMOylation provides a principal driving force for cellular stress responses, including DNA-protein crosslink (DPC) repair and arsenic-induced PML body degradation. In this study, using genome-scale screens, we identified the human E3 ligase TOPORS as a key effector of SUMO-dependent DPC resolution. We demonstrate that TOPORS promotes DPC repair by functioning as a SUMO-targeted ubiquitin ligase (STUbL), combining ubiquitin ligase activity through its RING domain with poly-SUMO binding via SUMO-interacting motifs, analogous to the STUbL RNF4. Mechanistically, TOPORS is a SUMO1-selective STUbL that complements RNF4 in generating complex ubiquitin landscapes on SUMOylated targets, including DPCs and PML, stimulating efficient p97/VCP unfoldase recruitment and proteasomal degradation. Combined loss of TOPORS and RNF4 is synthetic lethal even in unstressed cells, involving defective clearance of SUMOylated proteins from chromatin accompanied by cell cycle arrest and apoptosis. Our findings establish TOPORS as a STUbL whose parallel action with RNF4 defines a general mechanistic principle in crucial cellular processes governed by direct SUMO-ubiquitin crosstalk.
Identifiants
pubmed: 38649616
doi: 10.1038/s41594-024-01294-7
pii: 10.1038/s41594-024-01294-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Vertegaal, A. C. O. Signalling mechanisms and cellular functions of SUMO. Nat. Rev. Mol. Cell Biol. 23, 715–731 (2022).
pubmed: 35750927
doi: 10.1038/s41580-022-00500-y
Zhao, X. SUMO-mediated regulation of nuclear functions and signaling processes. Mol. Cell 71, 409–418 (2018).
pubmed: 30075142
pmcid: 6095470
doi: 10.1016/j.molcel.2018.07.027
Chang, Y. C., Oram, M. K. & Bielinsky, A. K. SUMO-targeted ubiquitin ligases and their functions in maintaining genome stability. Int. J. Mol. Sci. 22, 5391 (2021).
pubmed: 34065507
pmcid: 8161396
doi: 10.3390/ijms22105391
Lecona, E. et al. USP7 is a SUMO deubiquitinase essential for DNA replication. Nat. Struct. Mol. Biol. 23, 270–277 (2016).
pubmed: 26950370
pmcid: 4869841
doi: 10.1038/nsmb.3185
Sriramachandran, A. M. et al. Arkadia/RNF111 is a SUMO-targeted ubiquitin ligase with preference for substrates marked with SUMO1-capped SUMO2/3 chain. Nat. Commun. 10, 3678 (2019).
pubmed: 31417085
pmcid: 6695498
doi: 10.1038/s41467-019-11549-3
Rojas-Fernandez, A. et al. SUMO chain-induced dimerization activates RNF4. Mol. Cell 53, 880–892 (2014).
pubmed: 24656128
pmcid: 3991395
doi: 10.1016/j.molcel.2014.02.031
Poulsen, S. L. et al. RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response. J. Cell Biol. 201, 797–807 (2013).
pubmed: 23751493
pmcid: 3678163
doi: 10.1083/jcb.201212075
Tatham, M. H. et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat. Cell Biol. 10, 538–546 (2008).
pubmed: 18408734
doi: 10.1038/ncb1716
Lallemand-Breitenbach, V. et al. Arsenic degrades PML or PML–RARα through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat. Cell Biol. 10, 547–555 (2008).
pubmed: 18408733
doi: 10.1038/ncb1717
Keiten-Schmitz, J., Schunck, K. & Muller, S. SUMO chains rule on chromatin occupancy. Front. Cell Dev. Biol. 7, 343 (2019).
pubmed: 31998715
doi: 10.3389/fcell.2019.00343
Borgermann, N. et al. SUMOylation promotes protective responses to DNA–protein crosslinks. EMBO J. 38, e101496 (2019).
Sun, Y. et al. A conserved SUMO pathway repairs topoisomerase DNA–protein cross-links by engaging ubiquitin-mediated proteasomal degradation. Sci. Adv. 6, eaba6290 (2020).
pubmed: 33188014
pmcid: 7673754
doi: 10.1126/sciadv.aba6290
Kuhbacher, U. & Duxin, J. P. How to fix DNA–protein crosslinks. DNA Repair (Amst.) 94, 102924 (2020).
pubmed: 32683310
doi: 10.1016/j.dnarep.2020.102924
Weickert, P. & Stingele, J. DNA–protein crosslinks and their resolution. Annu. Rev. Biochem. 91, 157–181 (2022).
pubmed: 35303790
doi: 10.1146/annurev-biochem-032620-105820
Liu, J. C. Y. et al. Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway. EMBO J. 40, e107413 (2021).
pubmed: 34346517
pmcid: 8441304
doi: 10.15252/embj.2020107413
Weickert, P. et al. SPRTN patient variants cause global-genome DNA–protein crosslink repair defects. Nat. Commun. 14, 352 (2023).
pubmed: 36681662
pmcid: 9867749
doi: 10.1038/s41467-023-35988-1
Santi, D. V., Norment, A. & Garrett, C. E. Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc. Natl Acad. Sci. USA 81, 6993–6997 (1984).
pubmed: 6209710
pmcid: 392062
doi: 10.1073/pnas.81.22.6993
Short, N. J. & Kantarjian, H. Hypomethylating agents for the treatment of myelodysplastic syndromes and acute myeloid leukemia: past discoveries and future directions. Am. J. Hematol. 97, 1616–1626 (2022).
pubmed: 35871436
doi: 10.1002/ajh.26667
Kroonen, J. S. et al. Inhibition of SUMOylation enhances DNA hypomethylating drug efficacy to reduce outgrowth of hematopoietic malignancies. Leukemia 37, 864–876 (2023).
Lallemand-Breitenbach, V., Zhu, J., Chen, Z. & de The, H. Curing APL through PML/RARA degradation by As
pubmed: 22056243
doi: 10.1016/j.molmed.2011.10.001
Arner, E. S. & Eriksson, S. Mammalian deoxyribonucleoside kinases. Pharmacol. Ther. 67, 155–186 (1995).
pubmed: 7494863
doi: 10.1016/0163-7258(95)00015-9
Steger, M. et al. Time-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale. Nat. Commun. 12, 5399 (2021).
pubmed: 34518535
pmcid: 8438043
doi: 10.1038/s41467-021-25454-1
Bushman, J. W. et al. Proteomics-based identification of DUB substrates using selective inhibitors. Cell Chem. Biol. 28, 78–87 e3 (2021).
pubmed: 33007217
doi: 10.1016/j.chembiol.2020.09.005
Turnbull, A. P. et al. Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature 550, 481–486 (2017).
pubmed: 29045389
pmcid: 6029662
doi: 10.1038/nature24451
Rajendra, R. et al. Topors functions as an E3 ubiquitin ligase with specific E2 enzymes and ubiquitinates p53. J. Biol. Chem. 279, 36440–36444 (2004).
pubmed: 15247280
doi: 10.1074/jbc.C400300200
Weger, S., Hammer, E. & Heilbronn, R. Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo. FEBS Lett. 579, 5007–5012 (2005).
pubmed: 16122737
doi: 10.1016/j.febslet.2005.07.088
Pungaliya, P. et al. TOPORS functions as a SUMO-1 E3 ligase for chromatin-modifying proteins. J. Proteome Res. 6, 3918–3923 (2007).
pubmed: 17803295
doi: 10.1021/pr0703674
Secombe, J. & Parkhurst, S. M. Drosophila topors is a RING finger-containing protein that functions as a ubiquitin-protein isopeptide ligase for the hairy basic helix-loop-helix repressor protein. J. Biol. Chem. 279, 17126–17133 (2004).
pubmed: 14871887
doi: 10.1074/jbc.M310097200
Park, H. J. et al. Identification of phosphorylation sites of TOPORS and a role for serine 98 in the regulation of ubiquitin but not SUMO E3 ligase activity. Biochemistry 47, 13887–13896 (2008).
pubmed: 19053840
doi: 10.1021/bi801904q
Rasheed, Z. A., Saleem, A., Ravee, Y., Pandolfi, P. P. & Rubin, E. H. The topoisomerase I-binding RING protein, topors, is associated with promyelocytic leukemia nuclear bodies. Exp. Cell. Res. 277, 152–160 (2002).
pubmed: 12083797
doi: 10.1006/excr.2002.5550
Haluska, P. Jr. et al. Interaction between human topoisomerase I and a novel RING finger/arginine–serine protein. Nucleic Acids Res. 27, 2538–2544 (1999).
pubmed: 10352183
pmcid: 148458
doi: 10.1093/nar/27.12.2538
Du, Z. et al. DNMT1 stability is regulated by proteins coordinating deubiquitination and acetylation-driven ubiquitination. Sci. Signal. 3, ra80 (2010).
pubmed: 21045206
pmcid: 3116231
doi: 10.1126/scisignal.2001462
Felle, M. et al. The USP7/Dnmt1 complex stimulates the DNA methylation activity of Dnmt1 and regulates the stability of UHRF1. Nucleic Acids Res. 39, 8355–8365 (2011).
pubmed: 21745816
pmcid: 3201865
doi: 10.1093/nar/gkr528
Qin, W., Leonhardt, H. & Spada, F. Usp7 and Uhrf1 control ubiquitination and stability of the maintenance DNA methyltransferase Dnmt1. J. Cell. Biochem. 112, 439–444 (2011).
pubmed: 21268065
doi: 10.1002/jcb.22998
Gonzalez-Prieto, R. et al. Global non-covalent SUMO interaction networks reveal SUMO-dependent stabilization of the non-homologous end joining complex. Cell Rep. 34, 108691 (2021).
pubmed: 33503430
doi: 10.1016/j.celrep.2021.108691
Plechanovova, A. et al. Mechanism of ubiquitylation by dimeric RING ligase RNF4. Nat. Struct. Mol. Biol. 18, 1052–1059 (2011).
pubmed: 21857666
pmcid: 3326525
doi: 10.1038/nsmb.2108
Chen, Z. & Pickart, C. M. A 25-kilodalton ubiquitin carrier protein (E2) catalyzes multi-ubiquitin chain synthesis via lysine 48 of ubiquitin. J. Biol. Chem. 265, 21835–21842 (1990).
pubmed: 2174887
doi: 10.1016/S0021-9258(18)45815-2
Middleton, A. J. & Day, C. L. The molecular basis of lysine 48 ubiquitin chain synthesis by Ube2K. Sci. Rep. 5, 16793 (2015).
pubmed: 26592444
pmcid: 4655369
doi: 10.1038/srep16793
Nakasone, M. A. et al. Structure of UBE2K–Ub/E3/polyUb reveals mechanisms of K48-linked Ub chain extension. Nat. Chem. Biol. 18, 422–431 (2022).
pubmed: 35027744
pmcid: 8964413
doi: 10.1038/s41589-021-00952-x
Jaffray, E. G. et al. The p97/VCP segregase is essential for arsenic-induced degradation of PML and PML–RARA. J. Cell Biol. 222, e202201027 (2023).
pubmed: 36880596
pmcid: 10005898
doi: 10.1083/jcb.202201027
Sarkari, F., Wang, X., Nguyen, T. & Frappier, L. The herpesvirus associated ubiquitin specific protease, USP7, is a negative regulator of PML proteins and PML nuclear bodies. PLoS ONE 6, e16598 (2011).
pubmed: 21305000
pmcid: 3031599
doi: 10.1371/journal.pone.0016598
Beskow, A. et al. A conserved unfoldase activity for the p97 AAA-ATPase in proteasomal degradation. J. Mol. Biol. 394, 732–746 (2009).
pubmed: 19782090
doi: 10.1016/j.jmb.2009.09.050
van den Boom, J. & Meyer, H. VCP/p97-mediated unfolding as a principle in protein homeostasis and signaling. Mol. Cell 69, 182–194 (2018).
pubmed: 29153394
doi: 10.1016/j.molcel.2017.10.028
Lange, S. M. et al. Comprehensive approach to study branched ubiquitin chains reveals roles for K48-K63 branches in VCP/p97-related processes. Preprint at bioRxiv https://doi.org/10.1101/2023.01.10.523363 (2023).
Wilson, M. D., Saponaro, M., Leidl, M. A. & Svejstrup, J. Q. MultiDsk: a ubiquitin-specific affinity resin. PLoS ONE 7, e46398 (2012).
pubmed: 23056298
pmcid: 3463603
doi: 10.1371/journal.pone.0046398
Aguilar-Martinez, E. et al. Screen for multi-SUMO–binding proteins reveals a multi-SIM–binding mechanism for recruitment of the transcriptional regulator ZMYM2 to chromatin. Proc. Natl Acad. Sci. USA 112, E4854–E4863 (2015).
pubmed: 26283374
pmcid: 4568223
doi: 10.1073/pnas.1509716112
Blomen, V. A. et al. Gene essentiality and synthetic lethality in haploid human cells. Science 350, 1092–1096 (2015).
pubmed: 26472760
doi: 10.1126/science.aac7557
Sakaue-Sawano, A. et al. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell 132, 487–498 (2008).
pubmed: 18267078
doi: 10.1016/j.cell.2007.12.033
Lecona, E. & Fernandez-Capetillo, O. A SUMO and ubiquitin code coordinates protein traffic at replication factories. Bioessays 38, 1209–1217 (2016).
pubmed: 27667742
doi: 10.1002/bies.201600129
Branigan, E., Plechanovova, A., Jaffray, E. G., Naismith, J. H. & Hay, R. T. Structural basis for the RING-catalyzed synthesis of K63-linked ubiquitin chains. Nat. Struct. Mol. Biol. 22, 597–602 (2015).
pubmed: 26148049
pmcid: 4529489
doi: 10.1038/nsmb.3052
Lightcap, E. S. et al. A small-molecule SUMOylation inhibitor activates antitumor immune responses and potentiates immune therapies in preclinical models. Sci. Transl. Med. 13, eaba7791 (2021).
pubmed: 34524860
pmcid: 9719791
doi: 10.1126/scitranslmed.aba7791
Oliveira, R. I., Guedes, R. A. & Salvador, J. A. R. Highlights in USP7 inhibitors for cancer treatment. Front. Chem. 10, 1005727 (2022).
pubmed: 36186590
pmcid: 9520255
doi: 10.3389/fchem.2022.1005727
Carette, J. E. et al. Ebola virus entry requires the cholesterol transporter Niemann–Pick C1. Nature 477, 340–343 (2011).
pubmed: 21866103
pmcid: 3175325
doi: 10.1038/nature10348
Ma, H. T. & Poon, R. Y. Synchronization of HeLa cells. Methods Mol. Biol. 761, 151–161 (2011).
pubmed: 21755447
doi: 10.1007/978-1-61779-182-6_10
Poulsen, M., Lukas, C., Lukas, J., Bekker-Jensen, S. & Mailand, N. Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks. J. Cell Biol. 197, 189–199 (2012).
pubmed: 22492721
pmcid: 3328375
doi: 10.1083/jcb.201109100
Tatham, M. H. et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J. Biol. Chem. 276, 35368–35374 (2001).
pubmed: 11451954
doi: 10.1074/jbc.M104214200
Haahr, P. et al. Actin maturation requires the ACTMAP/C19orf54 protease. Science 377, 1533–1537 (2022).
pubmed: 36173861
doi: 10.1126/science.abq5082
Brockmann, M. et al. Genetic wiring maps of single-cell protein states reveal an off-switch for GPCR signalling. Nature 546, 307–311 (2017).
pubmed: 28562590
doi: 10.1038/nature22376
Lackner, D. H. et al. A generic strategy for CRISPR–Cas9-mediated gene tagging. Nat. Commun. 6, 10237 (2015).
pubmed: 26674669
doi: 10.1038/ncomms10237
Vizcaino, J. A. et al. ProteomeXchange provides globally coordinated proteomics data submission and dissemination. Nat. Biotechnol. 32, 223–226 (2014).
pubmed: 24727771
pmcid: 3986813
doi: 10.1038/nbt.2839