Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition.

Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance

Live-Cell Imaging of Cellular Proteins by a Strain-Promoted Azide–Alkyne Cycloaddition

Live and let dye: Three coumarin-cyclooctyne conjugates have been used to label proteins tagged with azidohomoalanine in Rat-1 fibroblasts. All three fluorophores labeled intracellular proteins with fluorescence enhancements ranging from eight- to 20-fold. These conjugates are powerful tools for visualizing biomolecule dynamics in living cells

A model for a pulsed terahertz quantum cascade laser under optical feedback

Optical feedback effects in lasers may be useful or problematic, depending on the type of application. When semiconductor lasers are operated using pulsed-mode excitation, their behavior under optical feedback depends on the electronic and thermal characteristics of the laser, as well as the nature of the external cavity. Predicting the behavior of a laser under both optical feedback and pulsed operation therefore requires a detailed model that includes laser-specific thermal and electronic characteristics. In this paper we introduce such a model for an exemplar bound-to-continuum terahertz frequency quantum cascade laser (QCL), illustrating its use in a selection of pulsed operation scenarios. Our results demonstrate significant interplay between electro-optical, thermal, and feedback phenomena, and that this interplay is key to understanding QCL behavior in pulsed applications. Further, our results suggest that for many types of QCL in interferometric applications, thermal modulation via low duty cycle pulsed operation would be an alternative to commonly used adiabatic modulation

Drosha drives the formation of DNA:RNA hybrids around DNA break sites to facilitate DNA repair

The error-free and efficient repair of DNA double-stranded breaks (DSBs) is extremely important for cell survival. RNA has been implicated in the resolution of DNA damage but the mechanism remains poorly understood. Here, we show that miRNA biogenesis enzymes, Drosha and Dicer, control the recruitment of repair factors from multiple pathways to sites of damage. Depletion of Drosha significantly reduces DNA repair by both homologous recombination (HR) and non-homologous end joining (NHEJ). Drosha is required within minutes of break induction, suggesting a central and early role for RNA processing in DNA repair. Sequencing of DNA:RNA hybrids reveals RNA invasion around DNA break sites in a Drosha-dependent manner. Removal of the RNA component of these structures results in impaired repair. These results show how RNA can be a direct and critical mediator of DNA damage repair in human cells