Stimulated cells and cancer cells have widespread shortening of mRNA 3’-untranslated regions (3’UTRs) and switches to shorter mRNA isoforms due to usage of more proximal polyadenylation signals (PASs) in introns and last exons. U1 snRNP (U1), vertebrates’ most abundant non-coding (spliceosomal) small nuclear RNA, silences proximal PASs and its inhibition with antisense morpholino oligonucleotides (U1 AMO) triggers widespread premature transcription termination and mRNA shortening. Here we show that low U1 AMO doses increase cancer cells’ migration and invasion in vitro by up to 500%, whereas U1 over-expression has the opposite effect. In addition to 3’UTR length, numerous transcriptome changes that could contribute to this phenotype are observed, including alternative splicing, and mRNA expression levels of proto-oncogenes and tumor suppressors. These findings reveal an unexpected role for U1 homeostasis (available U1 relative to transcription) in oncogenic and activated cell states, and suggest U1 as a potential target for their modulation.

DNA double-strand break (DSB) repair via homologous recombination is initiated by end resection. The extent of DNA end resection determines the choice of the DSB repair pathway. Nucleases for end resection have been extensively studied. However, it is still unclear how the potential DNA structures generated by the initial short resection by MRE11-RAD50-NBS1 are recognized and recruit proteins, such as EXO1, to DSB sites to facilitate long-range resection. We found that the MSH2-MSH3 mismatch repair complex is recruited to DSB sites through interaction with the chromatin remodeling protein SMARCAD1. MSH2-MSH3 facilitates the recruitment of EXO1 for long-range resection and enhances its enzymatic activity. MSH2-MSH3 also inhibits access of POLθ, which promotes polymerase theta-mediated end-joining (TMEJ). Collectively, we present a direct role of MSH2-MSH3 in the initial stages of DSB repair by promoting end resection and influencing the DSB repair pathway by favoring homologous recombination over TMEJ.

Despite global efforts to reduce plastic consumption, its usage continues to rise, leading to increased environmental contamination and heightened concerns regarding the potential health impacts of nanoplastics. Owing to their prolonged residence time in the intestine, nanoplastics contribute to prolonged exposure and absorption by intestinal epithelial cells. In this study, we examined the effects of polystyrene micro- and nanoplastics of varying sizes (20 nm-1000 nm) on colorectal cancer cells (HCT116) through a series of in vitro experiments, including cell viability assays, morphological assessments, and transcriptomic profiling. Notably, long-term exposure of HCT116 cells to small-sized (20 nm) nanoplastics at a low-dose, one that does not cause acute toxicity, led to significant morphological changes and gene expression alterations. These modifications included the upregulation of markers associated with migration, cancer stem cell (CSC) properties, and epithelial-mesenchymal transition (EMT). The enhanced expression of migration markers correlated with increased cell motility. Consistent with these in vitro findings, zebrafish models demonstrated accelerated metastasis of colorectal cancer cells following nanoplastic exposure. Collectively, these results suggest that nanoplastics may contribute to colorectal cancer progression, providing new insights into the molecular mechanisms underlying this process.