Terence Strick
Molecular Motors and Machines
Contexte
Single-molecule approaches to the study of biological systems have provided unprecedented insights into the kinetic and strutural properties of the molecules of life such as nucleic acids and proteins. By zooming in on individual molecules one can monitor their interactions in real-time and observe the variability and fluctuations which underlie the diversity of outcomes in molecular interactions. One can even begin to observe the differences which exist between molecules which are nominatively identical, for instance resulting from misfolding, post-translational modifications or damage for instance.
Single-molecule experimentation broadly falls into two categories : nanomanipulation and fluorescence. Each method has distinct advantages and disadvantages ; nanomanipulation allows one to probe molecules by applying mechanical forces to them and enables one to detect successful molecular interactions and biochemical reactions — in essence, to "see" what the nanomanipulated molecule is "doing". However it is difficult to simultaneously nanomanipulate multiple species of molecules in a single experiment. Single-molecule fluorescence allows one to observe multiple molecules simultaneously, but can sometimes be limited in its ability to report on what exactly the interacting molecules were doing to each other during the interaction. The combination of the two approaches, while technically challenging, is therefore extremely complementary and provides exciting new avenues of research into the assembly, activity, and disassembly of dynamic molecular complexes.
Key Results
Our group uses these approaches to study the biological activities of DNA such as its transcription, replication and repair. In recent years our work has focused in particular on the complex molecular reactions which allow DNA to be repaired. Indeed the genome which is safeguarded in the nucleus of each one of our cells is constantly undergoing damage (e.g. from various forms of radiation, chemical carcinogens, but also some "natural" processes such as antibody maturation) and must constantly be repaired. We have thus characterized in molecular detail two key DNA repair pathways which repair DNA, respectively, from UV radiation and chemical carcinogens (such as those contained in tobacco smoke or overcooked foods), and from ionizing radiation. Understanding these repair processes has fundamental importance for instance to understanding cancer and improving itst treatments, but it will also be a key challenge if we are to send humans into space where they are unprotected by the earth’s magnetic field from hard ionization radiation ("cosmic rays").
Kostrz D, Maynard SA, Camuso S, Schulte C, Laurent F, Masson JB, Maric HM, Gosse C, Triller A, Strick TR, Specht CG. Competition between glycine and GABAA receptors for gephyrin controls their equilibrium populations at inhibitory synapses. Proc Natl Acad Sci U S A. 2025 122(52):e2500226122. doi : 10.1073/pnas.2500226122. Epub 2025 Dec 23. PMID : 41433069 ; PMCID : PMC12771574.
Yun L, Garnier F, Strick TR, Nadal M. Deciphering the human TopIIIα activity modulated by Rmi1 using magnetic tweezers. Nucleic Acids Res. (2025) 53(8):gkaf308. doi : 10.1093/nar/gkaf308. PMID : 40266687 ; PMCID : PMC12016800.
Xiong Y, Han W, Xu C, Shi J, Wang L, Jin T, Jia Q, Lu Y, Hu S, Dou SX, Lin W, Strick TR, Wang S, Li M. Single-molecule reconstruction of eukaryotic factor-dependent transcription termination. Nat Commun. (2024) 15:5113. doi : 10.1038/s41467-024-49527-z. PMID : 38879529 ; PMCID : PMC11180205.
Vayssières M, Marechal N, Yun L, Lopez Duran B, Murugasamy NK, Fogg JM, Zechiedrich L, Nadal M, Lamour V. Structural basis of DNA crossover capture by Escherichia coli DNA gyrase. Science. 2024 384:227-232. doi : 10.1126/science.adl5899. Epub 2024 Apr 11. PMID : 38603484 ; PMCID : PMC11108255.
Stransky F, Kostrz D, Follenfant M, Pomplun S, Meyners C, Strick T, Hausch F, Gosse C. Use of DNA forceps to measure receptor-ligand dissociation equilibrium constants in a single-molecule competition assay. Methods Enzymol. (2024) 694:51-82. doi : 10.1016/bs.mie.2024.01.010. Epub 2024 Feb 27. PMID : 38492958.
Wang S, Han Z, Strick TR. Single-molecule characterization of Sen1 translocation properties provides insights into eukaryotic factor-dependent transcription termination. Nucleic Acids Res. (2024) 52:3249-3261. doi : 10.1093/nar/gkae026. PMID : 38261990 ; PMCID : PMC11013386.
Portman JR, Qayyum MZ, Murakami KS, Strick TR. On the stability of stalled RNA polymerase and its removal by RapA. Nucleic Acids Res. (2022) 50:7396-7405. doi : 10.1093/nar/gkac558. PMID : 35819188 ; PMCID : PMC9303389.
Portman JR, Brouwer GM, Bollins J, Savery NJ, Strick TR. Cotranscriptional R-loop formation by Mfd involves topological partitioning of DNA. Proc Natl Acad Sci U S A. (2021). 118:e2019630118.
Öz R, Wang JL, Guerois R, Goyal G, Kk S, Ropars V, Sharma R, Koca F, Charbonnier JB, Modesti M, Strick TR, Westerlund F. Dynamics of Ku and bacterial non-homologous end-joining characterized using single DNA molecule analysis. Nucleic Acids Res. (2021). 49:2629-2641.
Yang X, Garnier F, Débat H, Strick TR, Nadal M. Direct observation of helicase-topoisomerase coupling within reverse gyrase. Proc Natl Acad Sci U S A. (2020). 117:10856-10864
Thapar R, Wang JL, Hammel M, Ye R, Liang K, Sun C, Hnizda A, Liang S, Maw SS, Lee L, Villarreal H, Forrester I, Fang S, Tsai MS, Blundell TL, Davis AJ, Lin C, Lees-Miller SP, Strick TR, Tainer JA. Mechanism of efficient double-strand break repair by a long non-coding RNA. Nucleic Acids Res. (2020) 48:10953-10972.
Couturier M, Gadelle D, Forterre P, Nadal M, Garnier F. The reverse gyrase TopR1 is responsible for the homeostatic control of DNA supercoiling in the hyperthermophilic archaeon Sulfolobus solfataricus. Mol Microbiol. (2020) 113:356-368.
Mardenborough YSN, Nitsenko K, Laffeber C, Duboc C, Sahin E, Quessada-Vial A, Winterwerp HHK, Sixma TK, Kanaar R, Friedhoff P, Strick TR, Lebbink JHG. The unstructured linker arms of MutL enable GATC site incision beyond roadblocks during initiation of DNA mismatch repair. Nucleic Acids Res. (2019) 47:11667-11680.
Kostrz D, Wayment-Steele HK, Wang JL, Follenfant M, Pande VS, Strick TR, Gosse C. A modular DNA scaffold to study protein-protein interactions at single-molecule resolution. Nat Nanotechnol. (2019) 14:988-993.
J. Fan, M. Leroux-Coyau, N.J. Savery and T.R. Strick. Reconstruction of bacterial transcription- coupled repair at single-molecule resolution Nature (2016). 536 : 234-7.
C. Duboc and E.T. Graves and T.R. Strick
Simple calibration of TIR field depth using the supercoiling response of DNA. Methods 105 : 56-61 (2016).
E.T. Graves, C. Duboc, J. Fan, F. Stransky, M. Leroux-Coyau and T.R. Strick
A dynamic DNA-repair complex observed by correlative single-molecule nanomanipulation and fluorescence. Nature Struct. Mol. Biol. 22 : 452—457 (2015).
