Search

Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR–Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1as the top hit that confers differential dropout effects in vitro and in vivo. MEN1knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8+T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin–MLL interaction reduces tumor growth in a CD8+T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1and provide a rationale for targeting MEN1in solid cancers.

Current models suggest that DNA double-strand breaks (DSBs) can move to the nuclear periphery for repair. It is unclear to what extent human DSBs display such repositioning. Here we show that the human nuclear envelope localizes to DSBs in a manner depending on DNA damage response (DDR) kinases and cytoplasmic microtubules acetylated by α-tubulin acetyltransferase-1 (ATAT1). These factors collaborate with the linker of nucleoskeleton and cytoskeleton complex (LINC), nuclear pore complex (NPC) protein NUP153, nuclear lamina and kinesins KIF5B and KIF13B to generate DSB-capturing nuclear envelope tubules (dsbNETs). dsbNETs are partly supported by nuclear actin filaments and the circadian factor PER1 and reversed by kinesin KIFC3. Although dsbNETs promote repair and survival, they are also co-opted during poly(ADP-ribose) polymerase (PARP) inhibition to restrain BRCA1-deficient breast cancer cells and are hyper-induced in cells expressing the aging-linked lamin A mutant progerin. In summary, our results advance understanding of nuclear structure–function relationships, uncover a nuclear–cytoplasmic DDR and identify dsbNETs as critical factors in genome organization and stability.

GNL1 inhibits cell apoptosis and promotes cell growth by inducing cytoplasmic retention and stabilization of p21 through AKT-mediated phosphorylation. Our data elucidate a novel GNL1/AKT/p21 signaling cascade to provide a growth benefit to cancer cells and this may be an ideal target for cancer therapeutic intervention.