Biology subjects

Communal, L.

Publications and source records attributed to Communal, L..

2 recordsLinked to original sources

bioRxiv2024

Localized translation of cell junction mRNAs is required for epithelial cell polarity

Epithelial cells exhibit a highly polarized organization along their apico-basal axis, a feature that is critical to their function and frequently perturbed in cancer. One less explored process modulating epithelial cell polarity is the subcellular localization of mRNA molecules. In the present study, we report that several mRNAs encoding evolutionarily conserved epithelial polarity regulatory proteins, including Zo-1, Afdn and Scrib, are localized to cell junction regions in Drosophila epithelial tissues and human epithelial cells. Targeting of these mRNAs is coincident with the robust junctional distribution of their encoded proteins, and we demonstrate that they are locally translated at cell junction regions. To identify RNA binding proteins (RBPs) potentially implicated in junctional mRNA regulation, we performed systematic immuno-labeling with a collection of validated RBP antibodies, identifying a dozen RBPs with consistent junctional distribution patterns, several of which directly bind junctional transcripts. Strikingly, depletion of these RBP candidates, including MAGOH, a core component of the exon-junction complex (EJC), perturbed the junctional distribution and localized translation of Zo-1 and Scrib mRNAs, as well as the junctional accumulation of their protein products. Functional disruption of MAGO, or its interaction partner Y14, in Drosophila follicular epithelial cells perturbs the distribution of junctional transcripts and proteins. Finally, tissue microarray analysis of ovarian cancer tumor specimens revealed that expression of MAGOH and ZO-1 is positively correlated and that both proteins are potential biomarkers of good prognosis. Altogether, this work reveals that localized mRNA translation at cell junction regions is important for modulating epithelial cell polarity. HIGHLIGHTSO_LICell junction mRNA targeting is conserved between tissues and species C_LIO_LIThese mRNAs undergo localized translation at areas of cell-cell contact C_LIO_LIA diversity of RBPs localize to cell junction regions and interact with junctional transcripts. C_LIO_LIDisruption of junctional RBPs impacts epithelial cell polarity and localized translation C_LIO_LIMAGOH and ZO-1 expression is correlated in ovarian tumor specimens and are potential biomarkers of good prognosis C_LI

molecular biology↗

bioRxiv2023

53BP1 mediates sensitivity to chemotherapy and is associated with poor clinical outcomes in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) remains the most lethal gynecological malignancy in North American women. At a cellular level, the current first-line chemotherapies cause DNA-damage and activate the DNA damage response signalling cascade. Here we explore the role of 53BP1, a central mediator of the DNA damage response, in HGSOC chemotherapy outcomes. Tissue 53BP1 protein levels were quantified in two independent HGSOC cohorts, the COEUR validation cohort (n = 173) and CHUM cohort (n = 56). Univariate and multivariate analyses showed that high nuclear 53BP1 levels in ovarian cancer cells were strongly associated with poor disease-specific survival in both cohorts. High 53BP1 was associated with poor progression-free survival (PFS) in the COEUR cohort, and trended towards poor PFS in the CHUM cohort. These findings were validated by whole-tumour TP53BP1 mRNA of the TCGA Firehose Legacy cohort (n = 591) in which high TP53BP1 mRNA levels were associated with poor overall survival on multivariate analysis. In HGSOC cell lines, 53BP1 levels were positively correlated with resistance to carboplatin using colony formation assay, and depletion of 53BP1 sensitized resistant cell lines to genotoxic therapies. These results suggest that 53BP1 is associated with poor prognosis in HGSOC and may mediate this relationship by modulating cellular sensitivity to chemotherapy. Statement of translational relevanceCurrent first-line chemotherapies in ovarian cancer cause DNA damage and activate the DNA damage response, culminating in the taking of cell fate decisions. 53BP1 is a central mediator in this signalling cascade, where it is involved at multiple levels: signal amplification, recruitment of effectors, DNA repair pathway choice, and cell cycle regulation. However, its role in ovarian cancer treatment outcomes remains unknown. In this study, we found that 53BP1 correlated with poor clinical outcomes in three ovarian cancer patient cohorts and mediated carboplatin sensitivity in ovarian cancer cells. These results reveal 53BP1 and the DNA damage response as important actors in ovarian cancer treatment response. Though further studies are necessary to gain a more complete understanding of their involvement in clinical outcomes, they appear as promising candidates for potential therapeutic targeting in ovarian cancer.

cancer biology↗