Sebastian studied Biology, Molecular and Cell Biology and Biochemistry at the Universities of Jena and Heidelberg (Germany) and undertook his MSc research with Dr Giulio Superti-Furga at EMBL.
For his PhD project, Sebastian joined Dr Richard Treisman’s laboratory at the London Research Institute of Cancer Research UK (now part of the Francis Crick Institute) where he studied how actin controls MRTF-A, a transcriptional coactivator of Serum Response Factor (SRF).
For his postdoctoral research, he joined the laboratories of Dr Frank Sicheri and Dr Tony Pawson at the Samuel Lunenfeld Research Institute in Toronto, Canada. There, Sebastian uncovered the structural basis of the substrate targeting mechanism to the poly(ADP-ribose)polymerase tankyrase, thereby enabling the successful prediction of novel tankyrase substrates and explaining why mutations in the adaptor protein 3BP2 cause cherubism, a rare human disease.
In October 2012, Sebastian joined the Divisions of Structural and Cancer Biology at the ICR. His laboratory studies how ADP-ribosylation regulates cell signalling, in particular Wnt/β-catenin signalling and telomere homeostasis, using a combination of biochemistry, structural biology and cell biology approaches.
Sebastian gained the title of Reader in 2019 and in 2022 was promoted to Professor. He serves as the Deputy Head of the Division of Structural Biology at the ICR.
Publications
ADP-ribosyltransferases, an update on function and nomenclature.
Lüscher B, Ahel I, Altmeyer M, Ashworth A, Bai P, Chang P, Cohen M, Corda D, Dantzer F, Daugherty MD, Dawson TM, Dawson VL, Deindl S, Fehr AR, Feijs KLH, Filippov DV, Gagné JP, Grimaldi G, Guettler S, Hoch NC, Hottiger MO, Korn P, Kraus WL, Ladurner A, Lehtiö L, Leung AKL, Lord CJ, Mangerich A, Matic I, Matthews J, Moldovan GL, Moss J, Natoli G, Nielsen ML, Niepel M, Nolte F, Pascal J, Paschal BM, Pawłowski K, Poirier GG, Smith S, Timinszky G, Wang ZQ, Yélamos J, Yu X, Zaja R, Ziegler M
The FEBS Journal, 2022, 289 (23), 7399-7410
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Reconstitution of the destruction complex defines roles of AXIN polymers and APC in β-catenin capture, phosphorylation, and ubiquitylation.
Ranes M, Zaleska M, Sakalas S, Knight R, Guettler S
Molecular Cell, 2021, 81 (16), 3246-3261.e11
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Solution NMR assignment of the ARC4 domain of human tankyrase 2.
Zaleska M, Pollock K, Collins I, Guettler S, Pfuhl M
Biomolecular NMR Assignments, 2019, 13 (1), 255-260
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CEA expression heterogeneity and plasticity confer resistance to the CEA-targeting bispecific immunotherapy antibody cibisatamab (CEA-TCB) in patient-derived colorectal cancer organoids.
Gonzalez-Exposito R, Semiannikova M, Griffiths B, Khan K, Barber LJ, Woolston A, Spain G, von Loga K, Challoner B, Patel R, Ranes M, Swain A, Thomas J, Bryant A, Saffery C, Fotiadis N, Guettler S, Mansfield D, Melcher A, Powles T, Rao S, Watkins D, Chau I, Matthews N, Wallberg F, Starling N, Cunningham D, Gerlinger M
Journal for Immunotherapy of Cancer, 2019, 7 (1), 101
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Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer.
Woolston A, Khan K, Spain G, Barber LJ, Griffiths B, Gonzalez-Exposito R, Hornsteiner L, Punta M, Patil Y, Newey A, Mansukhani S, Davies MN, Furness A, Sclafani F, Peckitt C, Jiménez M, Kouvelakis K, Ranftl R, Begum R, Rana I, Thomas J, Bryant A, Quezada S, Wotherspoon A, Khan N, Fotiadis N, Marafioti T, Powles T, Lise S, Calvo F, Guettler S, von Loga K, Rao S, Watkins D, Starling N, Chau I, Sadanandam A, Cunningham D, Gerlinger M
Cancer Cell, 2019, 36 (1), 35-50.e9
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Fragment-based screening identifies molecules targeting the substrate-binding ankyrin repeat domains of tankyrase.
Pollock K, Liu M, Zaleska M, Meniconi M, Pfuhl M, Collins I, Guettler S
Scientific Reports, 2019, 9 (1), 19130
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Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance.
Pettitt SJ, Krastev DB, Brandsma I, Dréan A, Song F, Aleksandrov R, Harrell MI, Menon M, Brough R, Campbell J, Frankum J, Ranes M, Pemberton HN, Rafiq R, Fenwick K, Swain A, Guettler S, Lee JM, Swisher EM, Stoynov S, Yusa K, Ashworth A, Lord CJ
Nature Communications, 2018, 9 (1), 1849
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Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment.
Xiong S, Lorenzen K, Couzens AL, Templeton CM, Rajendran D, Mao DYL, Juang YC, Chiovitti D, Kurinov I, Guettler S, Gingras AC, Sicheri F
Structure (London, England : 1993), 2018, 26 (8), 1101-1115.e6
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Regulation of Protein Interactions by Mps One Binder (MOB1) Phosphorylation.
Xiong S, Couzens AL, Kean MJ, Mao DY, Guettler S, Kurinov I, Gingras AC, Sicheri F
Molecular & Cellular Proteomics : MCP, 2017, 16 (6), 1111-1125
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MOB1 Mediated Phospho-recognition in the Core Mammalian Hippo Pathway.
Couzens AL, Xiong S, Knight JDR, Mao DY, Guettler S, Picaud S, Kurinov I, Filippakopoulos P, Sicheri F, Gingras AC
Molecular & Cellular Proteomics : MCP, 2017, 16 (6), 1098-1110
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Identifying and Validating Tankyrase Binders and Substrates: A Candidate Approach.
Pollock K, Ranes M, Collins I, Guettler S
Methods in Molecular Biology (Clifton, N.J.), 2017, 1608, 445-473
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Regulation of Wnt/β-catenin signalling by tankyrase-dependent poly(ADP-ribosyl)ation and scaffolding.
Mariotti L, Pollock K, Guettler S
British Journal of Pharmacology, 2017, 174 (24), 4611-4636
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Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.
Mariotti L, Templeton CM, Ranes M, Paracuellos P, Cronin N, Beuron F, Morris E, Guettler S
Molecular Cell, 2016, 63 (3), 498-513
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AXIN Shapes Tankyrase ARChitecture.
Guettler S
Structure (London, England : 1993), 2016, 24 (10), 1625-1627
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The genomic landscape of oesophagogastric junctional adenocarcinoma.
Chong IY, Cunningham D, Barber LJ, Campbell J, Chen L, Kozarewa I, Fenwick K, Assiotis I, Guettler S, Garcia-Murillas I, Awan S, Lambros M, Starling N, Wotherspoon A, Stamp G, Gonzalez-de-Castro D, Benson M, Chau I, Hulkki S, Nohadani M, Eltahir Z, Lemnrau A, Orr N, Rao S, Lord CJ, Ashworth A
The Journal of Pathology, 2013, 231 (3), 301-10
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Structure of a pentavalent G-actin*MRTF-A complex reveals how G-actin controls nucleocytoplasmic shuttling of a transcriptional coactivator.
Mouilleron S, Langer CA, Guettler S, McDonald NQ, Treisman R
Science Signaling, 2011, 4 (177), ra40
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Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function.
Persaud A, Alberts P, Hayes M, Guettler S, Clarke I, Sicheri F, Dirks P, Ciruna B, Rotin D
The EMBO Journal, 2011, 30 (16), 3259-73
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Structural basis and sequence rules for substrate recognition by Tankyrase explain the basis for cherubism disease.
Guettler S, LaRose J, Petsalaki E, Gish G, Scotter A, Pawson T, Rottapel R, Sicheri F
Cell, 2011, 147 (6), 1340-54
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RPEL motifs link the serum response factor cofactor MAL but not myocardin to Rho signaling via actin binding.
Guettler S, Vartiainen MK, Miralles F, Larijani B, Treisman R
Molecular and Cellular Biology, 2008, 28 (2), 732-42
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Molecular basis for G-actin binding to RPEL motifs from the serum response factor coactivator MAL.
Mouilleron S, Guettler S, Langer CA, Treisman R, McDonald NQ
The EMBO Journal, 2008, 27 (23), 3198-208
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Nuclear actin regulates dynamic subcellular localization and activity of the SRF cofactor MAL.
Vartiainen MK, Guettler S, Larijani B, Treisman R
Science (New York, N.Y.), 2007, 316 (5832), 1749-52
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Mutant actins that stabilise F-actin use distinct mechanisms to activate the SRF coactivator MAL.
Posern G, Miralles F, Guettler S, Treisman R
The EMBO Journal, 2004, 23 (20), 3973-83
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A myristoyl/phosphotyrosine switch regulates c-Abl.
Hantschel O, Nagar B, Guettler S, Kretzschmar J, Dorey K, Kuriyan J, Superti-Furga G
Cell, 2003, 112 (6), 845-57
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ESTs from the basidiomycete Schizophyllum commune grown on nitrogen-replete and nitrogen-limited media.
Guettler S, Jackson EN, Lucchese SA, Honaas L, Green A, Hittinger CT, Tian Y, Lilly WW, Gathman AC
Fungal Genetics and Biology : FG & B, 2003, 39 (2), 191-8
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