Actin Dynamics Couples Extracellular Signals to the Mobility and Molecular Stability of Telomeres

Genome regulatory programs such as telomere functioning require extracellular signals to be transmitted from the microenvironment to the nucleus and chromatin. Although the cytoskeleton has been shown to directly transmit stresses, we show that the intrinsically dynamic nature of the actin cytoskeleton is important in relaying extracellular signals to telomeres. Interestingly, this mechanical pathway not only transmits physical stimuli but also chemical stimuli. The cytoskeletal network continuously reorganizes and applies dynamic forces on the nucleus and feeds into the regulation of telomere dynamics. We further found that distal telomeres are mechanically coupled in a length- and timescale-dependent manner and identified nesprin 2G as well as lamin A/C as being essential to regulate their translational dynamics. Finally, we demonstrated that such mechanotransduction events impinge on the binding dynamics of critical telomere binding proteins. Our results highlight an overarching physical pathway that regulates positional and molecular stability of telomeres.