“Understanding and targeting SMC function has diverse therapeutic applications, from antimicrobials to cancer”
Our research interest is focused on the function of the three eukaryotic SMC complexes; cohesin, condensin and Smc5/6. Structural Maintenance of Chromosomes (SMC) complexes are sophisticated machines capable of remodelling chromosome architecture during the essential processes of the cell cycle. They form ring-shaped structures and use ATP hydrolysis to fuel their manipulation in order to change the topology of chromatin fibers. SMC function is therefore closely linked to that of topoisomerases. The ability to manipulate DNA allows SMC complexes to alter local chromatin structure cooperatively to ensure that higher-order manipulation of chromosomes is achieved as required during distinct cellular processes. We use biochemical and biophysical techniques on purified proteins to investigate mechanisms of SMC complex function, and combine these in vitro approaches with studies in yeast and human cells to gain an understanding of the function of these protein complexes inside eukaryotic cells.
SMC complexes are essential in eukaryotic and bacterial cells, therefore inhibitors of SMC function, and associated factors (i.e. topoisomerases), have diverse therapeutic applications, from antimicrobials to cancer. We interested in the translational potential of SMC complexes and are currently working on the “reverse antibiotic” nybomycin for the treatment of fluoroquinolone-resistance (antimicrobial resistance – AMR) infections.
Diagrammatic representation of the ‘reverse antibiotic’ concept. Ciprofloxacin (a fluoroquinolone antibiotic) is an effective treatment of wild type S. aureus shown in blue. Target mutations lead to a mutant strain, shown in red, that is resistant to ciprofloxacin. Deoxynybomycin (a reverse antibiotic) can then be used to treat the mutant S. aureus.
Studies on the SMC complex condensin. DNA compaction trace for single-molecule experiments using optical tweezers for λ-DNA molecule extended using a force of 1pN (top). The DNA was tethered between two beads. One bead was clamped (fixed) while a 1pN force was applied to the second bead to maintain the molecule extended. The DNA was then incubated in the presence of 1nM condensin (1mM ATP in 50mM NaCl) (left- magenta trace). The FE curve for the λ-DNA full extension after incubation is shown (bottom). Cryo-EM structure of yeast condensin tetramer.
Gutierrez-Escribano P, Hormeño S, Madariaga-Marcos J, Solé-Soler R, O’Reilly F, Morris K, Aicart-Ramos C, Aramayo R, Montoya A, Kramer H, Rappsilber J, Torres-Rosell J, Moreno-Herrero F, Aragon L. (2020). Purified Smc5/6 Complex Exhibits DNA Substrate Recognition and Compaction. Molecular Cell 80 (6), 1039-1054.
Lee B-G, Merkel F, Allegretti M, Hassler M, Cawood C, Lecomte L, O’Reilly F, Sinn L, Gutierrez-Escribano P, Kschonsak M, Bravo S, Nakane T, Rappsilber J, Aragon L*, Beck M*, Löwe J*, Haering C.* (2020). Cryo-EM structures of holo condensin reveal a subunit flip-flop mechanism. Nature Structural and Molecular Biology 27, 743-751.
Bardell-Cox O, White AJP, Aragon L*, Fuchter MJ. * (2019). Synthetic studies on the reverse antibiotic natural products, the nybomycins. Med Chem Commun 10 (8), 1438-1444.
Gutierrez-Escribano P, Newton M, Llauro A, Huber J, Tanasie L, Davy J, Aly I, Aramayo R, Montoya A, Kramer H, Stigler J, Rueda D, Aragón L. (2019). A conserved ATP and Scc2/4-dependent activity for cohesin in tethering DNA molecules. Science Advances 5 (11), eaay6804.
Garcia-Luis J, Lazar-Stefanita L, Gutierrez-Escribano P, Thierry A, Garcia A, Sanchez M, Jarmuz A, Montoya A, Dore M, Kramer H, Karimi M, Antequera F, Koszul R, Aragón L. (2019). FACT mediates cohesin function on chromatin. Nature Structural and Molecular Biology 26, 970-979
Sen N, Leonard J, Torres R, Garcia-Luis J, Palou-Marin G, Aragón L. (2016). Physical Proximity of Sister Chromatids Promotes Top2-Dependent Intertwining, Molecular Cell 64(1), 134-147.