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RAD-TGTs: Measurement of cellular tensions via flow cytometry and DNA sequencing enabled by force-dependent rupture and delivery of DNA tension probes

Pawlak, M. R.; Smiley, A. T.; Kelly, M. D.; Shamsan, G. A.; Anderson, S. M.; Smeester, B. A.; Largaespada, D. A.; Odde, D. J.; Gordon, W. R.

2022-11-08 biophysics
10.1101/2022.11.08.515662 bioRxiv
Show abstract

Mechanical force is a key driver of cellular processes and is dysregulated in many diseases. Measuring cellular tensions to elucidate mechanotransduction pathways typically involves high-resolution but low throughput imaging of surfaces and arduous experimental preparation of materials. We present here Rupture and Deliver DNA-duplex based molecular tension sensors-RAD-TGTs. RAD-TGTs consist of immobilized DNA duplexes conjugated to a ligand and indicator (fluorophore, barcode etc) which rupture in a force-dependent manner when cells are bound. Readout of rupture is performed in cells of interest using high throughput methods such as flow cytometry and leveraging covalent DNA-protein linking HUH-tags simplifies the preparation of the tension sensor to allow use of "off-the-shelf" oligos. We demonstrate that rupture and delivery is decreased by inhibitors of cytoskeletal dynamics and knockout of mechanosensing proteins. We also show that rupture and delivery correlates with ligand affinity. Excitingly, we demonstrate that rupture and delivery of barcoded DNA-duplexes can be quantified using DNA sequencing, propelling cellular force measurements into the -omics era.

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