Stress granules promote quiescence by enhancing p21 levels and reducing phospho-Rb.

During the integrated stress response (ISR), most mRNAs exit translation and some condense into stress granules. Stress granules that form during chemotherapy can promote cancer cell survival and chemoresistance by an unknown mechanism. Cells can also spontaneously trigger the ISR at low levels, which promotes cellular quiescence where cells exit the cell cycle and are resistant to therapeutic agents. We hypothesized that the ability of cells to form stress granules might be a critical signal to drive cells into quiescence. Herein, we provide several observations that suggest stress granules enhance cell survival and chemoresistance by promoting cellular quiescence. The mechanism by which stress granules promote quiescence is by stimulating p21 expression, leading to inhibition of Rb phosphorylation. These results demonstrate that stress granule formation is sufficient to trigger cellular quiescence and argue that inhibitors of stress granules may be effective in combination with chemotherapy to limit the development of chemoresistance in treating human tumors.