Biology subjects

Cappell, S. D.

Publications and source records attributed to Cappell, S. D..

2 recordsLinked to original sources

bioRxiv2020

Targeting nuclear pore protein, NUP210, reduces metastasis through heterochromatin-mediated silencing of mechanosensitive genes

Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identified nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Nup210 depletion suppresses lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with LINC complex protein SUN2 which connects the nucleus to the cytoskeleton. In addition, the NUP210/SUN2 complex interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. In Nup210 knockout cells, mechanosensitive genes accumulate H3K27me3 heterochromatin modification, mediated by the polycomb repressive complex 2 and differentially reposition within the nucleus. Transcriptional repression in Nup210 knockout cells results in defective mechanotransduction and focal adhesion necessary for their metastatic capacity. Our study provides a new insight into the role of nuclear pore protein in cellular mechanosensation and metastasis.

cancer biology↗

bioRxiv2019

Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

U2AF1 forms a heterodimeric complex with U2AF2 that is primarily responsible for 3 splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome and Acute Myeloid Leukemia, and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). However, the U2AF heterodimer also has a non-canonical function as a translational regulator. Here, we report that the U2AF1 S34F mutation results in specific mis-regulation of the translation initiation and ribosome biogenesis machinery, with the potential for widespread translational changes. The net result is a global increase in mRNA translation at the single cell level. Among the translationally upregulated targets of U2AF1-S34F are Nucleophosmin1 (NPM1), which is a major driver of myeloid malignancy. Depletion of NPM1 impairs the viability of wt/S34F cells and causes rRNA processing defects, thus indicating an unanticipated synthetic interaction between U2AF1, NPM1 and ribosome biogenesis. Our results establish a unique molecular phenotype for the U2AF1 mutation which recapitulates translational mis-regulation in myeloid disease.

cell biology↗