Post-transcriptional regulation of the breast cancer susceptibility gene BRCA1 by Hu Antigen-R

BRCA1 is a breast cancer susceptibility gene that is down-regulated in the majority of cases of sporadic breast cancer. In tumours with reduced BRCA1 protein expression, there can be a concomitant reduction in mRNA level, or no change, suggesting that disruption of multiple different regulatory processes may contribute to BRCA1 down-regulation. Despite this, efforts to date have chiefly focussed on transcriptional and epigenetic regulation of the gene, whilst post-transcriptional processes that regulate the dynamics of the BRCA1 transcript, such as decay, localisation and translation efficiency, are poorly understood. Post-transcriptional regulation of gene expression is often mediated by RNA-binding proteins (RNA-BPs) that recognise sequence motifs in the untranslated regions (UTRs) of certain mRNAs, and recruit, or shield them from macromolecular complexes involved in RNA metabolism, such as the translation apparatus and the exosome. Primary and secondary structure analysis of the BRCA1 3'UTR sequence revealed two predicted binding sites for the RNA-BP Hu-antigen R (HuR), known to regulate the stability and translation efficiency of other transcripts, including COX-2, TNF-α and TP53. Interestingly, HuR is frequently over-expressed in sporadic breast cancer. We present the results of RNA-protein-binding assays showing that HuR interacts directly with synthetic RNA probes containing one of the predicted HuR-binding sites in the BRCA1 3'UTR, and immunoprecipitation studies showing that this interaction occurs endogenously in human mammary epithelial cell lines. Over-expression of HuR conferred a reduction in BRCA1 protein expression, and the BRCA1 3'UTR sequence was sufficient for down-regulation of a luciferase reporter gene in cells expressing ectopic HuR. Experiments addressing the mechanism underlying the change in BRCA1 expression in HuR over-expressing cells, including reporter assays, mRNA and protein stability assays, suggest that the mechanism of regulation is post-transcriptional. Current and future work is aimed at understanding the relationship between HuR and BRCA1 in breast cancer

A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction

Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region