Planar compression of extracellular substrates induces S phase arrest via ATM-independent CHK2 activation

Cell proliferation is regulated not only by soluble chemical factors but also by mechanical cues surrounding cells. Mechanical stretch of extracellular substrates is known to promote cell proliferation by driving exit from the G₀ phase and entry into the S phase. Here, we report that planer compression of extracellular substrates induces cell cycle arrest in the S phase. The compression-induced S phase arrest is mediated by the checkpoint kinase 2 (CHK2)-p53 pathway. In contrast to the canonical S phase checkpoint pathway activated by DNA damage, CHK2 activation by the substrate compression is independent of ataxia telangiectasia mutated (ATM). We further find that disassembly of the actin cytoskeleton is required for the compression-induced S phase arrest. Notably, cancer cells do not exhibit S phase arrest upon the substrate compression. Our results suggest a novel mechanism for homeostatic control of cell growth under mechanical perturbations.