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Terence Strick

Molecular Motors and Machines


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").

Selected publications

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.

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.

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.

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

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.

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.

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.

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).

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).