Stress granules (SG) are cytoplasmic RNA granules that form during various types of stress known to inhibit general translation, including oxidative stress, hypoxia, endoplasmic reticulum stress (ER), ionizing radiations or viral infection. Induction of these SG promotes cell survival in part through sequestration of proapoptotic molecules, resulting in the inactivation of cell death pathways. SG also form in cancer cells, but studies investigating their formation upon treatment with chemotherapeutics are very limited. Here we identified Lapatinib (Tykerb / Tyverb ®), a tyrosine kinase inhibitor used for the treatment of breast cancers as a new inducer of SG in breast cancer cells. Lapatinib-induced SG formation correlates with the inhibition of general translation initiation which involves the phosphorylation of the translation initiation factor eIF2α through the kinase PERK. Disrupting PERK-SG formation by PERK depletion experiments sensitizes resistant breast cancer cells to Lapatinib. This study further supports the assumption that treatment with anticancer drugs activates the SG pathway, which may constitute an intrinsic stress response used by cancer cells to resist treatment.

The Fragile X Mental Retardation Protein (FMRP) is a canonical RNA-binding protein whose absence in humans leads to the development of the Fragile X Syndrome characterized by multiple phenotypes including neurodevelopmental disorders, intellectual disability, autism, and macroorchidism. The primary transcripts of the FMR1 gene undergo extensive alternative splicing processes, and multiple protein isoforms are produced. The predominantly cytoplasmic isoforms are translational regulators, while the roles of the nuclear ones have been neglected. In this study, we discovered that nuclear FMRP isoforms specifically associate with DNA bridges, aberrant genomic structures that form during mitosis and whose accumulation can drive genome instability by inducing DNA damage. Further localisation studies showed that a subset of FMRP-positive bridges contain proteins that have been shown to associate with specific DNA bridges known as ultrafine DNA bridges (UFBs), and surprisingly are RNA positive. Significantly, the depletion of nuclear FMRP isoforms promotes the accumulation of DNA bridges, correlating with the accumulation of DNA damages and cell death, unveiling an important function of these neglected isoforms.