{"entity": "researcher", "timestamp": "2026-07-19T05:57:30.352Z", "family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "affiliations": ["Science for Life Laboratory, Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.", "Unit of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c"}}, "publications": [{"entity": "publication", "iuid": "5aa825a515bd4748afa8d655ebf3d0ac", "links": {"self": {"href": "https://publications.scilifelab.se/publication/5aa825a515bd4748afa8d655ebf3d0ac.json"}, "display": {"href": "https://publications.scilifelab.se/publication/5aa825a515bd4748afa8d655ebf3d0ac"}}, "title": "NUDT5 regulates the global efficacy of nucleoside analog drugs by coordinating purine synthesis and PRPP allocation", "authors": [{"family": "Valerie", "given": "Nicholas C K", "initials": "NCK", "orcid": "0000-0002-9423-964X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f1d90c5a1f924c8b97409934dec74b0b.json"}}, {"family": "Alam", "given": "Seher", "initials": "S", "orcid": "0000-0002-8494-832X", "researcher": {"href": "https://publications.scilifelab.se/researcher/034588861fbc437bafe9cf7074ecd7ab.json"}}, {"family": "Hormann", "given": "Femke M", "initials": "FM", "orcid": "0000-0001-5164-3047", "researcher": {"href": "https://publications.scilifelab.se/researcher/79446287545b419aa569359af34b23ce.json"}}, {"family": "Martens", "given": "Ulf", "initials": "U"}, {"family": "Lundgren", "given": "Bo", "initials": "B"}, {"family": "Gaetani", "given": "Massimiliano", "initials": "M", "orcid": "0000-0001-5610-0797", "researcher": {"href": "https://publications.scilifelab.se/researcher/7b58e5cef5224fdcbdcd626fb798b169.json"}}, {"family": "Bostr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0001-5252-4023", "researcher": {"href": "https://publications.scilifelab.se/researcher/2af59464d2c74c27af7a43fb5d1a670e.json"}}, {"family": "Rudd", "given": "Sean G", "initials": "SG", "orcid": "0000-0002-4368-3855", "researcher": {"href": "https://publications.scilifelab.se/researcher/cf1e23d9748e4868a4b5e966e423b1a9.json"}}, {"family": "Arvidsson", "given": "Per I", "initials": "PI", "orcid": "0000-0002-9453-6812", "researcher": {"href": "https://publications.scilifelab.se/researcher/ae064b90b750457e80e974947f2dfc7a.json"}}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}], "type": "posted-content", "published": "2025-11-20", "journal": {"title": "biorxiv", "issn": null, "issn-l": null, "volume": null, "issue": null, "pages": null}, "abstract": null, "doi": "10.1101/2025.11.20.689348", "pmid": null, "labels": {"Chemical Proteomics": "Collaborative"}, "xrefs": [], "notes": [], "created": "2025-11-25T16:34:20.317Z", "modified": "2025-12-18T18:33:55.727Z"}, {"entity": "publication", "iuid": "6e499e6478cc4696a5a0a6a7534b3c6c", "links": {"self": {"href": "https://publications.scilifelab.se/publication/6e499e6478cc4696a5a0a6a7534b3c6c.json"}, "display": {"href": "https://publications.scilifelab.se/publication/6e499e6478cc4696a5a0a6a7534b3c6c"}}, "title": "A cell-based degrader assessment platform facilitates discovery of functional NUDT5 PROTACs", "authors": [{"family": "Alam", "given": "Seher", "initials": "S", "orcid": "0000-0002-8494-832X", "researcher": {"href": "https://publications.scilifelab.se/researcher/034588861fbc437bafe9cf7074ecd7ab.json"}}, {"family": "Pires", "given": "Maria J", "initials": "MJ", "orcid": "0009-0007-0384-091X", "researcher": {"href": "https://publications.scilifelab.se/researcher/9e7a891756624e5583914ea7b2d3176e.json"}}, {"family": "Tidestav", "given": "Gabriel", "initials": "G"}, {"family": "Jemth", "given": "Ann Sofie", "initials": "AS", "orcid": "0000-0002-7550-1833", "researcher": {"href": "https://publications.scilifelab.se/researcher/fd07c6c543544af1a904e039f73ba857.json"}}, {"family": "Eklund", "given": "Julia", "initials": "J", "orcid": "0009-0000-7449-2456", "researcher": {"href": "https://publications.scilifelab.se/researcher/96b04b6202964265b671901bcf4b66b4.json"}}, {"family": "Klingeg\u00e5rd", "given": "Fredrik", "initials": "F", "orcid": "0000-0001-6280-3894", "researcher": {"href": "https://publications.scilifelab.se/researcher/87593a4ce9ba4b3d8d1e3bc6836d42af.json"}}, {"family": "Caraballo", "given": "R\u00e9mi", "initials": "R", "orcid": "0000-0001-5912-8429", "researcher": {"href": "https://publications.scilifelab.se/researcher/9e3194cd076e4eac95e029cfe4adefbc.json"}}, {"family": "Gaetani", "given": "Massimiliano", "initials": "M", "orcid": "0000-0001-5610-0797", "researcher": {"href": "https://publications.scilifelab.se/researcher/7b58e5cef5224fdcbdcd626fb798b169.json"}}, {"family": "Rotilli", "given": "Dante", "initials": "D", "orcid": "0000-0002-8428-8763", "researcher": {"href": "https://publications.scilifelab.se/researcher/4939561c24b14fbbbdd82aa08a9e1ab5.json"}}, {"family": "van den Elzen", "given": "Siebe", "initials": "S"}, {"family": "van Berkum", "given": "Eri", "initials": "E"}, {"family": "Wallner", "given": "Olov", "initials": "O", "orcid": "0000-0002-6481-237X", "researcher": {"href": "https://publications.scilifelab.se/researcher/83eb2f7ee2f34f2cbacaae2dadcd90e9.json"}}, {"family": "Malmstr\u00f6m", "given": "Jonas", "initials": "J"}, {"family": "Arvidsson", "given": "Per I", "initials": "PI", "orcid": "0000-0002-9453-6812", "researcher": {"href": "https://publications.scilifelab.se/researcher/ae064b90b750457e80e974947f2dfc7a.json"}}, {"family": "Valerie", "given": "Nicholas C K", "initials": "NCK", "orcid": "0000-0002-9423-964X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f1d90c5a1f924c8b97409934dec74b0b.json"}}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}], "type": "posted-content", "published": "2025-06-19", "journal": {"title": "biorxiv", "issn": null, "issn-l": null, "volume": null, "issue": null, "pages": null}, "abstract": null, "doi": "10.1101/2025.06.13.659494", "pmid": null, "labels": {"Chemical Proteomics": "Collaborative"}, "xrefs": [], "notes": [], "created": "2025-11-25T16:38:01.820Z", "modified": "2025-12-18T19:14:22.271Z"}, {"entity": "publication", "iuid": "8f813a953a47489dbce089b11fc24f50", "links": {"self": {"href": "https://publications.scilifelab.se/publication/8f813a953a47489dbce089b11fc24f50.json"}, "display": {"href": "https://publications.scilifelab.se/publication/8f813a953a47489dbce089b11fc24f50"}}, "title": "Duplexed CeTEAM drug biosensors reveal determinants of PARP inhibitor selectivity in cells.", "authors": [{"family": "Pires", "given": "Maria J", "initials": "MJ"}, {"family": "Alam", "given": "Seher", "initials": "S"}, {"family": "Lovric", "given": "Alen", "initials": "A"}, {"family": "Fabbrizi", "given": "Emanuele", "initials": "E"}, {"family": "Rotili", "given": "Dante", "initials": "D"}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}, {"family": "Valerie", "given": "Nicholas C K", "initials": "NCK", "orcid": "0000-0002-9423-964X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f1d90c5a1f924c8b97409934dec74b0b.json"}}], "type": "journal article", "published": "2025-02-26", "journal": {"title": "J. Biol. Chem.", "issn": "1083-351X", "pages": "108361", "issn-l": "0021-9258"}, "abstract": "Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) targeting PARP1 and PARP2 have revolutionized cancer therapy by selectively killing cancer cells with defective DNA repair. However, achieving PARP1 or PARP2-selective inhibitors is difficult due to structural homology. Selectivity profiling is typically done with purified proteins, but these lack the complexity of intracellular environments and could therefore be inaccurate. Here, we duplex PARP1 L713F-GFP and PARP2 L269A-mCherry cellular target engagement by accumulation of mutant (CeTEAM) drug biosensors to systematically characterize binding and cell cycle alterations of 27 PARPi. Our results reveal that most PARPi are equipotent for both PARPs, including the next-generation drug, senaparib. However, benzimidazole carboxamide (niraparib) derivatives demonstrated PARP1-selective tendencies, while pthalazinones (olaparib) favored PARP2. AZD5305, a reported PARP1-selective inhibitor with characteristics of both series, was the exception and appears \u223c1600-fold more potent towards PARP1. In agreement with current understanding, we see that trapping-associated S/G2-phase transitions positively correlate with PARP1/2 binding potency, while some potent binders, such as veliparib, did not - likely reflecting their allosteric influence on DNA retention. We also assessed the effect of the PARP1/2 active site component, histone PARylation factor 1 (HPF1), on intracellular PARPi binding and see that HPF1 depletion elicits slight deviations in apparent binding potency, while contributing additively to trapping-like phenotypes. The PARP1/2 CeTEAM platform thus provides a structural roadmap for the development of selective PARPi and should facilitate the discovery of targeted therapies. Furthermore, our results highlight that multiplexing CeTEAM biosensors and layered genetic perturbations can systematically profile determinants of intracellular drug selectivity.", "doi": "10.1016/j.jbc.2025.108361", "pmid": "40021124", "labels": {"Chemical Biology Consortium Sweden": "Service"}, "xrefs": [{"db": "pii", "key": "S0021-9258(25)00210-8"}], "notes": [], "created": "2025-03-14T14:15:13.223Z", "modified": "2025-10-17T13:04:26.850Z"}, {"entity": "publication", "iuid": "6befcd3ead5a4b38aa1ed2b2a3efb705", "links": {"self": {"href": "https://publications.scilifelab.se/publication/6befcd3ead5a4b38aa1ed2b2a3efb705.json"}, "display": {"href": "https://publications.scilifelab.se/publication/6befcd3ead5a4b38aa1ed2b2a3efb705"}}, "title": "Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM.", "authors": [{"family": "Valerie", "given": "Nicholas C K", "initials": "NCK", "orcid": "0000-0002-9423-964X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f1d90c5a1f924c8b97409934dec74b0b.json"}}, {"family": "Sanjiv", "given": "Kumar", "initials": "K"}, {"family": "Mortusewicz", "given": "Oliver", "initials": "O", "orcid": "0000-0002-4290-4994", "researcher": {"href": "https://publications.scilifelab.se/researcher/b62a88fc39a54906a40e28e679c9f624.json"}}, {"family": "Zhang", "given": "Si Min", "initials": "SM", "orcid": "0000-0001-7763-603X", "researcher": {"href": "https://publications.scilifelab.se/researcher/1eac01c3a53d4940ade49b24f13dd214.json"}}, {"family": "Alam", "given": "Seher", "initials": "S"}, {"family": "Pires", "given": "Maria J", "initials": "MJ"}, {"family": "Stigsdotter", "given": "Hannah", "initials": "H"}, {"family": "Rasti", "given": "Azita", "initials": "A"}, {"family": "Langelier", "given": "Marie-France", "initials": "MF", "orcid": "0000-0001-9815-1840", "researcher": {"href": "https://publications.scilifelab.se/researcher/caac2647bbde41dbbd7d5fd31fb2da70.json"}}, {"family": "Rehling", "given": "Daniel", "initials": "D"}, {"family": "Throup", "given": "Adam", "initials": "A", "orcid": "0000-0001-6512-8679", "researcher": {"href": "https://publications.scilifelab.se/researcher/dea6b870fafa471499bd71f1b2693be4.json"}}, {"family": "Purewal-Sidhu", "given": "Oryn", "initials": "O"}, {"family": "Desroses", "given": "Matthieu", "initials": "M"}, {"family": "Onireti", "given": "Jacob", "initials": "J", "orcid": "0009-0003-9745-4446", "researcher": {"href": "https://publications.scilifelab.se/researcher/989eece269e544728082d7764d924d52.json"}}, {"family": "Wakchaure", "given": "Prasad", "initials": "P"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Bostr\u00f6m", "given": "Johan", "initials": "J"}, {"family": "Bevc", "given": "Luka", "initials": "L"}, {"family": "Benzi", "given": "Giorgia", "initials": "G"}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications.scilifelab.se/researcher/d97eba9f5edf4d76a5259c4baa8366c5.json"}}, {"family": "Pascal", "given": "John M", "initials": "JM", "orcid": "0000-0002-2714-4317", "researcher": {"href": "https://publications.scilifelab.se/researcher/ee603b6cd7984898bd6cdbb601e4b3e7.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d7256c271ea4adea404d4ff355f804e.json"}}, {"family": "Page", "given": "Brent D G", "initials": "BDG"}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}], "type": "journal article", "published": "2024-12-06", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "15", "issue": "1", "pages": "10347", "issn-l": "2041-1723"}, "abstract": "Cellular target engagement technologies enable quantification of intracellular drug binding; however, simultaneous assessment of drug-associated phenotypes has proven challenging. Here, we present cellular target engagement by accumulation of mutant as a platform that can concomitantly evaluate drug-target interactions and phenotypic responses using conditionally stabilized drug biosensors. We observe that drug-responsive proteotypes are prevalent among reported mutants of known drug targets. Compatible mutants appear to follow structural and biophysical logic that permits intra-protein and paralogous expansion of the biosensor pool. We then apply our method to uncouple target engagement from divergent cellular activities of MutT homolog 1 (MTH1) inhibitors, dissect Nudix hydrolase 15 (NUDT15)-associated thiopurine metabolism with the R139C pharmacogenetic variant, and profile the dynamics of poly(ADP-ribose) polymerase 1/2 (PARP1/2) binding and DNA trapping by PARP inhibitors (PARPi). Further, PARP1-derived biosensors facilitated high-throughput screening for PARP1 binders, as well as multimodal ex vivo analysis and non-invasive tracking of PARPi binding in live animals. This approach can facilitate holistic assessment of drug-target engagement by bridging drug binding events and their biological consequences.", "doi": "10.1038/s41467-024-54415-7", "pmid": "39643609", "labels": {"Chemical Biology Consortium Sweden": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC11624193"}, {"db": "pii", "key": "10.1038/s41467-024-54415-7"}], "notes": [], "created": "2024-12-16T08:43:06.953Z", "modified": "2025-10-17T13:04:27.012Z"}, {"entity": "publication", "iuid": "61fa13eeb4e7471fb3fc42d11ed00aeb", "links": {"self": {"href": "https://publications.scilifelab.se/publication/61fa13eeb4e7471fb3fc42d11ed00aeb.json"}, "display": {"href": "https://publications.scilifelab.se/publication/61fa13eeb4e7471fb3fc42d11ed00aeb"}}, "title": "Single-cell sequencing deconvolutes cellular responses to exercise in human skeletal muscle.", "authors": [{"family": "Lovri\u0107", "given": "Alen", "initials": "A"}, {"family": "Rassolie", "given": "Ali", "initials": "A"}, {"family": "Alam", "given": "Seher", "initials": "S"}, {"family": "Mandi\u0107", "given": "Mirko", "initials": "M"}, {"family": "Saini", "given": "Amarjit", "initials": "A"}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}, {"family": "Fernandez-Gonzalo", "given": "Rodrigo", "initials": "R"}, {"family": "Gustafsson", "given": "Thomas", "initials": "T"}, {"family": "Rullman", "given": "Eric", "initials": "E", "orcid": "0000-0003-2854-7262", "researcher": {"href": "https://publications.scilifelab.se/researcher/bf3c60e63af042eba26ce2732374fcdb.json"}}], "type": "journal article", "published": "2022-10-22", "journal": {"title": "Commun Biol", "issn": "2399-3642", "issn-l": "2399-3642", "volume": "5", "issue": "1", "pages": "1121"}, "abstract": "Skeletal muscle adaptations to exercise have been associated with a range of health-related benefits, but cell type-specific adaptations within the muscle are incompletely understood. Here we use single-cell sequencing to determine the effects of exercise on cellular composition and cell type-specific processes in human skeletal muscle before and after intense exercise. Fifteen clusters originating from six different cell populations were identified. Most cell populations remained quantitatively stable after exercise, but a large transcriptional response was observed in mesenchymal, endothelial, and myogenic cells, suggesting that these cells are specifically involved in skeletal muscle remodeling. We found three subpopulations of myogenic cells characterized by different maturation stages based on the expression of markers such as PAX7, MYOD1, TNNI1, and TNNI2. Exercise accelerated the trajectory of myogenic progenitor cells towards maturation by increasing the transcriptional features of fast- and slow-twitch muscle fibers. The transcriptional regulation of these contractile elements upon differentiation was validated in vitro on primary myoblast cells. The cell type-specific adaptive mechanisms induced by exercise presented here contribute to the understanding of the skeletal muscle adaptations triggered by physical activity and may ultimately have implications for physiological and pathological processes affecting skeletal muscle, such as sarcopenia, cachexia, and glucose homeostasis.", "doi": "10.1038/s42003-022-04088-z", "pmid": "36273106", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Production)": "Service", "NGI Short read": "Service", "Eukaryotic Single Cell Genomics (ESCG)": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Single cell": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC9588010"}, {"db": "pii", "key": "10.1038/s42003-022-04088-z"}], "notes": [], "created": "2022-12-19T10:36:03.073Z", "modified": "2023-10-16T12:41:05.413Z"}, {"entity": "publication", "iuid": "238d3aa204584626b4262aea39c30cc5", "links": {"self": {"href": "https://publications.scilifelab.se/publication/238d3aa204584626b4262aea39c30cc5.json"}, "display": {"href": "https://publications.scilifelab.se/publication/238d3aa204584626b4262aea39c30cc5"}}, "title": "Inhibition of the ubiquitin-proteasome system by an NQO1-activatable compound.", "authors": [{"family": "Giovannucci", "given": "Tatiana A", "initials": "TA", "orcid": "0000-0001-8978-6318", "researcher": {"href": "https://publications.scilifelab.se/researcher/56b2f3f196874ef8b62a8768286c136a.json"}}, {"family": "Salomons", "given": "Florian A", "initials": "FA"}, {"family": "Haraldsson", "given": "Martin", "initials": "M"}, {"family": "Elfman", "given": "Lotta H M", "initials": "LHM"}, {"family": "Wickstr\u00f6m", "given": "Malin", "initials": "M", "orcid": "0000-0001-5214-9956", "researcher": {"href": "https://publications.scilifelab.se/researcher/2bd8b895bc0a4dca89c4170f85d3ebb4.json"}}, {"family": "Young", "given": "Patrick", "initials": "P"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Eirich", "given": "J\u00fcrgen", "initials": "J", "orcid": "0000-0003-0963-1872", "researcher": {"href": "https://publications.scilifelab.se/researcher/ec48b74a3727482d944088601c310a38.json"}}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}, {"family": "Jafari", "given": "Rozbeh", "initials": "R", "orcid": "0000-0002-3396-4709", "researcher": {"href": "https://publications.scilifelab.se/researcher/481b2a2329634f9086cf52fb808edea5.json"}}, {"family": "Gustavsson", "given": "Anna-Lena", "initials": "AL"}, {"family": "Johnsen", "given": "John Inge", "initials": "JI", "orcid": "0000-0003-1277-812X", "researcher": {"href": "https://publications.scilifelab.se/researcher/4c5b7b4c780349afacf3063e311c334e.json"}}, {"family": "Dantuma", "given": "Nico P", "initials": "NP", "orcid": "0000-0002-6090-4170", "researcher": {"href": "https://publications.scilifelab.se/researcher/0ccdd02c787d4a699efd24d297040aa0.json"}}], "type": "journal article", "published": "2021-10-06", "journal": {"title": "Cell Death Dis", "issn": "2041-4889", "issn-l": "2041-4889", "volume": "12", "issue": "10", "pages": "914"}, "abstract": "Malignant cells display an increased sensitivity towards drugs that reduce the function of the ubiquitin-proteasome system (UPS), which is the primary proteolytic system for destruction of aberrant proteins. Here, we report on the discovery of the bioactivatable compound CBK77, which causes an irreversible collapse of the UPS, accompanied by a general accumulation of ubiquitylated proteins and caspase-dependent cell death. CBK77 caused accumulation of ubiquitin-dependent, but not ubiquitin-independent, reporter substrates of the UPS, suggesting a selective effect on ubiquitin-dependent proteolysis. In a genome-wide CRISPR interference screen, we identified the redox enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) as a critical mediator of CBK77 activity, and further demonstrated its role as the compound bioactivator. Through affinity-based proteomics, we found that CBK77 covalently interacts with ubiquitin. In vitro experiments showed that CBK77-treated ubiquitin conjugates were less susceptible to disassembly by deubiquitylating enzymes. In vivo efficacy of CBK77 was validated by reduced growth of NQO1-proficient human adenocarcinoma cells in nude mice treated with CBK77. This first-in-class NQO1-activatable UPS inhibitor suggests that it may be possible to exploit the intracellular environment in malignant cells for leveraging the impact of compounds that impair the UPS.", "doi": "10.1038/s41419-021-04191-9", "pmid": "34615851", "labels": {"CRISPR Functional Genomics": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Stockholm (Genomics Production)": "Service", "National Genomics Infrastructure": "Service", "Global Proteomics and Proteogenomics": "Service", "Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1038/s41419-021-04191-9"}, {"db": "pmc", "key": "PMC8494907"}], "notes": [], "created": "2021-10-16T09:54:38.919Z", "modified": "2025-10-17T13:04:28.026Z"}, {"entity": "publication", "iuid": "f18d7672bbbb4e5dbcd524fde4fbc995", "links": {"self": {"href": "https://publications.scilifelab.se/publication/f18d7672bbbb4e5dbcd524fde4fbc995.json"}, "display": {"href": "https://publications.scilifelab.se/publication/f18d7672bbbb4e5dbcd524fde4fbc995"}}, "title": "The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output.", "authors": [{"family": "Kanellis", "given": "Dimitris C", "initials": "DC", "orcid": "0000-0001-8690-2010", "researcher": {"href": "https://publications.scilifelab.se/researcher/0921ab7566514fb0a3cd0daf2baabe6e.json"}}, {"family": "Espinoza", "given": "Jaime A", "initials": "JA", "orcid": "0000-0002-0731-2715", "researcher": {"href": "https://publications.scilifelab.se/researcher/3cdf2cd80f5b4f87adf6d936b6390ee8.json"}}, {"family": "Zisi", "given": "Asimina", "initials": "A", "orcid": "0000-0002-4253-0275", "researcher": {"href": "https://publications.scilifelab.se/researcher/5cf82380ca6e4cd1985bc9dd23789539.json"}}, {"family": "Sakkas", "given": "Elpidoforos", "initials": "E"}, {"family": "Bartkova", "given": "Jirina", "initials": "J"}, {"family": "Katsori", "given": "Anna-Maria", "initials": "AM", "orcid": "0000-0002-5975-2931", "researcher": {"href": "https://publications.scilifelab.se/researcher/1a338e7f888b4e7fa663fdd87d667713.json"}}, {"family": "Bostr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0001-5252-4023", "researcher": {"href": "https://publications.scilifelab.se/researcher/2af59464d2c74c27af7a43fb5d1a670e.json"}}, {"family": "Dyrskj\u00f8t", "given": "Lars", "initials": "L"}, {"family": "Broholm", "given": "Helle", "initials": "H", "orcid": "0000-0002-6029-822X", "researcher": {"href": "https://publications.scilifelab.se/researcher/c6d1ef8a71f24d1694aee57b47c22198.json"}}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}, {"family": "Els\u00e4sser", "given": "Simon J", "initials": "SJ", "orcid": "0000-0001-8724-4849", "researcher": {"href": "https://publications.scilifelab.se/researcher/fcf26e35e037499aa1441a7738ba61af.json"}}, {"family": "Lindstr\u00f6m", "given": "Mikael S", "initials": "MS", "orcid": "0000-0003-1148-8497", "researcher": {"href": "https://publications.scilifelab.se/researcher/5aa942fbfbee4257a129b3e7888f5b6d.json"}}, {"family": "Bartek", "given": "Jiri", "initials": "J", "orcid": "0000-0003-2013-7525", "researcher": {"href": "https://publications.scilifelab.se/researcher/cd0d4d98261f41268c76dd91345a1857.json"}}], "type": "journal article", "published": "2021-08-00", "journal": {"title": "Sci Adv", "issn": "2375-2548", "volume": "7", "issue": "32", "issn-l": "2375-2548"}, "abstract": "Eukaryotic initiation factor 4A-III (eIF4A3), a core helicase component of the exon junction complex, is essential for splicing, mRNA trafficking, and nonsense-mediated decay processes emerging as targets in cancer therapy. Here, we unravel eIF4A3's tumor-promoting function by demonstrating its role in ribosome biogenesis (RiBi) and p53 (de)regulation. Mechanistically, eIF4A3 resides in nucleoli within the small subunit processome and regulates rRNA processing via R-loop clearance. EIF4A3 depletion induces cell cycle arrest through impaired RiBi checkpoint-mediated p53 induction and reprogrammed translation of cell cycle regulators. Multilevel omics analysis following eIF4A3 depletion pinpoints pathways of cell death regulation and translation of alternative mouse double minute homolog 2 (MDM2) transcript isoforms that control p53. EIF4A3 expression and subnuclear localization among clinical cancer specimens correlate with the RiBi status rendering eIF4A3 an exploitable vulnerability in high-RiBi tumors. We propose a concept of eIF4A3's unexpected role in RiBi, with implications for cancer pathogenesis and treatment.", "doi": "10.1126/sciadv.abf7561", "pmid": "34348895", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Production)": "Service", "NGI Stockholm (Genomics Applications)": "Service", "Global Proteomics and Proteogenomics": "Service"}, "xrefs": [{"db": "pii", "key": "7/32/eabf7561"}, {"db": "pmc", "key": "PMC8336962"}], "notes": [], "created": "2021-10-01T09:03:24.915Z", "modified": "2023-06-19T11:42:22.695Z"}, {"entity": "publication", "iuid": "08a45a5b61b8441ea51d9b53a518fc25", "links": {"self": {"href": "https://publications.scilifelab.se/publication/08a45a5b61b8441ea51d9b53a518fc25.json"}, "display": {"href": "https://publications.scilifelab.se/publication/08a45a5b61b8441ea51d9b53a518fc25"}}, "title": "Development of a chemical probe against NUDT15.", "authors": [{"family": "Zhang", "given": "Si Min", "initials": "SM", "orcid": "0000-0001-7763-603X", "researcher": {"href": "https://publications.scilifelab.se/researcher/1eac01c3a53d4940ade49b24f13dd214.json"}}, {"family": "Desroses", "given": "Matthieu", "initials": "M", "orcid": "0000-0003-4152-3855", "researcher": {"href": "https://publications.scilifelab.se/researcher/b232b70751004e9ea6b547533f901376.json"}}, {"family": "Hagenkort", "given": "Anna", "initials": "A"}, {"family": "Valerie", "given": "Nicholas C K", "initials": "NCK"}, {"family": "Rehling", "given": "Daniel", "initials": "D", "orcid": "0000-0002-8627-3469", "researcher": {"href": "https://publications.scilifelab.se/researcher/a4d521579d594e44b783a8d2e9fb98bb.json"}}, {"family": "Carter", "given": "Megan", "initials": "M"}, {"family": "Wallner", "given": "Olov", "initials": "O"}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Throup", "given": "Adam", "initials": "A"}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "AS"}, {"family": "Alml\u00f6f", "given": "Ingrid", "initials": "I"}, {"family": "Loseva", "given": "Olga", "initials": "O"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": "https://publications.scilifelab.se/researcher/e13df787cb884549bcf333aba4e6f010.json"}}, {"family": "Axelsson", "given": "Hanna", "initials": "H", "orcid": "0000-0003-2365-1749", "researcher": {"href": "https://publications.scilifelab.se/researcher/63b88c4d11c443f39121c6d93fcff1f0.json"}}, {"family": "Regmi", "given": "Shruti", "initials": "S"}, {"family": "Sarno", "given": "Antonio", "initials": "A"}, {"family": "Kr\u00e4mer", "given": "Andreas", "initials": "A"}, {"family": "Pudelko", "given": "Linda", "initials": "L"}, {"family": "Br\u00e4utigam", "given": "Lars", "initials": "L"}, {"family": "Rasti", "given": "Azita", "initials": "A"}, {"family": "G\u00f6ttmann", "given": "Mona", "initials": "M"}, {"family": "Wiita", "given": "Elis\u00e9e", "initials": "E"}, {"family": "Kutzner", "given": "Juliane", "initials": "J"}, {"family": "Schaller", "given": "Torsten", "initials": "T", "orcid": "0000-0001-9597-4112", "researcher": {"href": "https://publications.scilifelab.se/researcher/c74944db1b4f4fe4a09079f417f8eec6.json"}}, {"family": "Kalder\u00e9n", "given": "Christina", "initials": "C"}, {"family": "C\u00e1zares-K\u00f6rner", "given": "Armando", "initials": "A"}, {"family": "Page", "given": "Brent D G", "initials": "BDG"}, {"family": "Krimpenfort", "given": "Rosa", "initials": "R"}, {"family": "Eshtad", "given": "Saeed", "initials": "S", "orcid": "0000-0001-6763-4700", "researcher": {"href": "https://publications.scilifelab.se/researcher/edf4a705cae045feb64d1d9c7f8d9646.json"}}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}, {"family": "Rudd", "given": "Sean G", "initials": "SG", "orcid": "0000-0002-4368-3855", "researcher": {"href": "https://publications.scilifelab.se/researcher/cf1e23d9748e4868a4b5e966e423b1a9.json"}}, {"family": "Knapp", "given": "Stefan", "initials": "S", "orcid": "0000-0001-5995-6494", "researcher": {"href": "https://publications.scilifelab.se/researcher/c4d84c40612d48f280d4ead25558d835.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M"}, {"family": "Homan", "given": "Evert J", "initials": "EJ"}, {"family": "Berglund", "given": "Ulrika Warpman", "initials": "UW", "orcid": "0000-0002-6372-1396", "researcher": {"href": "https://publications.scilifelab.se/researcher/a74c79d4b11346a4918f536b5a678e12.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications.scilifelab.se/researcher/d97eba9f5edf4d76a5259c4baa8366c5.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d7256c271ea4adea404d4ff355f804e.json"}}], "type": "journal article", "published": "2020-10-00", "journal": {"title": "Nat. Chem. Biol.", "issn": "1552-4469", "volume": "16", "issue": "10", "pages": "1120-1128", "issn-l": "1552-4450"}, "abstract": "The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to elucidate its biological functions and potentially to improve NUDT15-dependent chemotherapeutics. Lead compound TH1760 demonstrated low-nanomolar biochemical potency through direct and specific binding into the NUDT15 catalytic pocket and engaged cellular NUDT15 in the low-micromolar range. We also employed thiopurine potentiation as a proxy functional readout and demonstrated that TH1760 sensitized cells to 6-thioguanine through enhanced accumulation of 6-thio-(d)GTP in nucleic acids. A biochemically validated, inactive structural analog, TH7285, confirmed that increased thiopurine toxicity takes place via direct NUDT15 inhibition. In conclusion, TH1760 represents the first chemical probe for interrogating NUDT15 biology and potential therapeutic avenues.", "doi": "10.1038/s41589-020-0592-z", "pmid": "32690945", "labels": {"Protein Science Facility (PSF)": "Service", "Chemical Biology Consortium Sweden": "Collaborative"}, "xrefs": [{"db": "pii", "key": "10.1038/s41589-020-0592-z"}, {"db": "pmc", "key": "PMC7610571"}, {"db": "mid", "key": "EMS118347"}], "notes": [], "created": "2020-09-25T11:44:11.217Z", "modified": "2025-10-17T13:04:28.262Z"}, {"entity": "publication", "iuid": "cde1f74c4f7c4f958deb3b63f5280f49", "links": {"self": {"href": "https://publications.scilifelab.se/publication/cde1f74c4f7c4f958deb3b63f5280f49.json"}, "display": {"href": "https://publications.scilifelab.se/publication/cde1f74c4f7c4f958deb3b63f5280f49"}}, "title": "Cell Cycle Profiling Reveals Protein Oscillation, Phosphorylation, and Localization Dynamics.", "authors": [{"family": "Herr", "given": "Patrick", "initials": "P", "orcid": "0000-0003-2945-966X", "researcher": {"href": "https://publications.scilifelab.se/researcher/ab7a8452d9464b48a74737f6615df015.json"}}, {"family": "Bostr\u00f6m", "given": "Johan", "initials": "J", "orcid": "0000-0001-5252-4023", "researcher": {"href": "https://publications.scilifelab.se/researcher/2af59464d2c74c27af7a43fb5d1a670e.json"}}, {"family": "Rullman", "given": "Eric", "initials": "E"}, {"family": "Rudd", "given": "Sean G", "initials": "SG", "orcid": "0000-0002-4368-3855", "researcher": {"href": "https://publications.scilifelab.se/researcher/cf1e23d9748e4868a4b5e966e423b1a9.json"}}, {"family": "Vesterlund", "given": "Mattias", "initials": "M", "orcid": "0000-0001-9471-6592", "researcher": {"href": "https://publications.scilifelab.se/researcher/0942e438993b494db2a3db914852c808.json"}}, {"family": "Lehti\u00f6", "given": "Janne", "initials": "J", "orcid": "0000-0002-8100-9562", "researcher": {"href": "https://publications.scilifelab.se/researcher/8406a97bac744a59b1bc951978994581.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d7256c271ea4adea404d4ff355f804e.json"}}, {"family": "Maddalo", "given": "Gianluca", "initials": "G"}, {"family": "Altun", "given": "Mikael", "initials": "M", "orcid": "0000-0002-6937-6124", "researcher": {"href": "https://publications.scilifelab.se/researcher/4317b773615e476694840e907b7b1a0c.json"}}], "type": "journal article", "published": "2020-04-00", "journal": {"title": "Mol. Cell Proteomics", "issn": "1535-9484", "volume": "19", "issue": "4", "pages": "608-623", "issn-l": "1535-9476"}, "abstract": "The cell cycle is a highly conserved process involving the coordinated separation of a single cell into two daughter cells. To relate transcriptional regulation across the cell cycle with oscillatory changes in protein abundance and activity, we carried out a proteome- and phospho-proteome-wide mass spectrometry profiling. We compared protein dynamics with gene transcription, revealing many transcriptionally regulated G2 mRNAs that only produce a protein shift after mitosis. Integration of CRISPR/Cas9 survivability studies further highlighted proteins essential for cell viability. Analyzing the dynamics of phosphorylation events and protein solubility dynamics over the cell cycle, we characterize predicted phospho-peptide motif distributions and predict cell cycle-dependent translocating proteins, as exemplified by the S-adenosylmethionine synthase MAT2A. Our study implicates this enzyme in translocating to the nucleus after the G1/S-checkpoint, which enables epigenetic histone methylation maintenance during DNA replication. Taken together, this data set provides a unique integrated resource with novel insights on cell cycle dynamics.", "doi": "10.1074/mcp.RA120.001938", "pmid": "32051232", "labels": {"Global Proteomics and Proteogenomics": "Collaborative"}, "xrefs": [{"db": "pii", "key": "S1535-9476(20)35020-9"}, {"db": "pmc", "key": "PMC7124475"}], "notes": [], "created": "2021-01-12T18:12:04.346Z", "modified": "2021-11-10T12:52:39.295Z"}, {"entity": "publication", "iuid": "675347d3c50d42f196d814d845d3b268", "links": {"self": {"href": "https://publications.scilifelab.se/publication/675347d3c50d42f196d814d845d3b268.json"}, "display": {"href": "https://publications.scilifelab.se/publication/675347d3c50d42f196d814d845d3b268"}}, "title": "MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.", "authors": [{"family": "Gad", "given": "Helge", "initials": "H", "orcid": "0000-0001-6530-1443", "researcher": {"href": "https://publications.scilifelab.se/researcher/6273ef3dd1574185af0a83e9ab31bfe5.json"}}, {"family": "Koolmeister", "given": "Tobias", "initials": "T"}, {"family": "Jemth", "given": "Ann-Sofie", "initials": "A", "orcid": "0000-0002-7550-1833", "researcher": {"href": "https://publications.scilifelab.se/researcher/fd07c6c543544af1a904e039f73ba857.json"}}, {"family": "Eshtad", "given": "Saeed", "initials": "S", "orcid": "0000-0001-6763-4700", "researcher": {"href": "https://publications.scilifelab.se/researcher/edf4a705cae045feb64d1d9c7f8d9646.json"}}, {"family": "Jacques", "given": "Sylvain A", "initials": "SA"}, {"family": "Str\u00f6m", "given": "Cecilia E", "initials": "CE"}, {"family": "Svensson", "given": "Linda M", "initials": "LM"}, {"family": "Schultz", "given": "Niklas", "initials": "N"}, {"family": "Lundb\u00e4ck", "given": "Thomas", "initials": "T", "orcid": "0000-0002-8145-7808", "researcher": {"href": 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"Martens", "given": "Ulf", "initials": "U"}, {"family": "Lundin", "given": "Cecilia", "initials": "C"}, {"family": "Lundgren", "given": "Bo", "initials": "B"}, {"family": "Granelli", "given": "Ingrid", "initials": "I"}, {"family": "Jensen", "given": "Annika Jenmalm", "initials": "AJ"}, {"family": "Artursson", "given": "Per", "initials": "P", "orcid": "0000-0002-3708-7395", "researcher": {"href": "https://publications.scilifelab.se/researcher/31575936c2714e1eb2f35c12df9a65a8.json"}}, {"family": "Nilsson", "given": "Jonas A", "initials": "JA", "orcid": "0000-0003-0346-6837", "researcher": {"href": "https://publications.scilifelab.se/researcher/27f0581f25124e98b0bd0eef8c3f3331.json"}}, {"family": "Stenmark", "given": "P\u00e5l", "initials": "P", "orcid": "0000-0003-4777-3417", "researcher": {"href": "https://publications.scilifelab.se/researcher/d97eba9f5edf4d76a5259c4baa8366c5.json"}}, {"family": "Scobie", "given": "Martin", "initials": "M", "orcid": "0000-0002-7073-8495", "researcher": {"href": "https://publications.scilifelab.se/researcher/87c041a8b3414f5db02873dc8013806b.json"}}, {"family": "Berglund", "given": "Ulrika Warpman", "initials": "UW", "orcid": "0000-0002-6372-1396", "researcher": {"href": "https://publications.scilifelab.se/researcher/a74c79d4b11346a4918f536b5a678e12.json"}}, {"family": "Helleday", "given": "Thomas", "initials": "T", "orcid": "0000-0002-7384-092X", "researcher": {"href": "https://publications.scilifelab.se/researcher/3d7256c271ea4adea404d4ff355f804e.json"}}], "type": "journal article", "published": "2014-04-10", "journal": {"volume": "508", "issn": "1476-4687", "issue": "7495", "pages": "215-221", "title": "Nature", "issn-l": "0028-0836"}, "abstract": "Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.", "doi": "10.1038/nature13181", "pmid": "24695224", "labels": {"Protein Science Facility (PSF)": null, "Chemical Biology Consortium Sweden": "Collaborative", "Drug Discovery and Development": "Collaborative"}, "xrefs": [{"db": "pii", "key": "nature13181"}], "notes": "Uppsala Drug Optimization and Pharmaceutical Profiling (UDOPP)\r\nADME of Therapeutics (UDOPP)\r\nBiochemical and Cellular Screening", "created": "2017-05-04T14:56:52.658Z", "modified": "2025-10-23T08:56:28.795Z"}]}