Hypoxia induces a vast array of long noncoding RNAs (lncRNA) in breast cancer cells, but their biological functions remain largely unknown. Here, we identified a hitherto uncharacterized hypoxiainduced lncRNA RAB11B-AS1 in breast cancer cells. RAB11B-AS1 is a natural lncRNA upregulated in human breast cancer and its expression is induced by hypoxia-inducible factor 2 (HIF2), but not HIF1, in response to hypoxia. RAB11B-AS1 enhanced the expression of angiogenic factors including VEGFA and ANGPTL4 in hypoxic breast cancer cells by increasing recruitment of RNA polymerase II. In line with increased angiogenic factors, conditioned media from RAB11B-AS1-overexpressing breast cancer cells promoted tube formation of human umbilical vein endothelial cells in vitro. Gain-and loss-of-function studies revealed that RAB11B-AS1 increased breast cancer cell migration and invasion in vitro and promoted tumor angiogenesis and breast cancer distant metastasis without affecting primary tumor growth in mice. Taken together, these findings uncover a fundamental mechanism of hypoxia-induced tumor angiogenesis and breast cancer metastasis.Significance: This study reveals the molecular mechanism by which the lncRNA RAB11B-AS1 regulates hypoxia-induced

A conserved stem-loop motif of the constitutive decay element (CDE) in the 3′ UTR of mRNAs is recognized by the ROQ domain of Roquin, which mediates their degradation. Here we report two crystal structures of the Homo sapiens ROQ domain in complex with CDE RNA. The ROQ domain has an elongated shape, with three sub-domains. The 19-nt Hmgxb3 CDE is bound as a stem-loop to domain III. The 23-nt TNF RNA is bound as a duplex, to a separate site at the interface between domains I and II. Mutagenesis studies confirm that the ROQ domain has two separate RNA binding sites, one for stem-loop RNA (A site) and the other for dsRNA (B site). Mutation in either site perturbs the Roquin-mediated degradation of HMGXB3 and IL-6 mRNAs in human cells, demonstrating the importance of both sites for mRNA decay.

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There are two known mRNA degradation pathways, 3' to 5' and 5' to 3'. We identified likely pathogenic variants in two genes involved in these two pathways in individuals with intellectual disability. In a large family with multiple branches, we identified biallelic variants in DCPS in three affected individuals; a splice site variant (c.636+1G>A) that results in an in-frame insertion of 45 nucleotides and a missense variant (c.947C>T; p.Thr316Met). DCPS decaps the cap structure generated by 3' to 5' exonucleolytic degradation of mRNA. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS. In another family, we identified a homozygous mutation (c.161T>C; p.Phe54Ser) in EDC3 in two affected children. EDC3 stimulates DCP2, which decaps mRNAs at the beginning of the 5' to 3' degradation pathway. In vitro decapping assays showed that altered EDC3 is unable to enhance DCP2 decapping at low concentrations and even inhibits DCP2 decapping at high concentration. We show that individuals with biallelic mutations in these genes of seemingly central functions are viable and that these possibly lead to impairment of neurological functions linking mRNA decapping to normal cognition. Our results further affirm an emerging theme linking aberrant mRNA metabolism to neurological defects.

Myogenic fate determination is important in skeletal muscle development, growth and repair. A variety of factors regulate myogenic cell determination via transcriptional and non-transcriptional mechanisms. Amongst these factors, long noncoding RNAs (lncRNAs) have gained considerable attention for their important roles in regulating myogenic differentiation and function. Many classes of lncRNAs have been discovered; various lncRNAs have been implicated in the regulation of myogenic cell fate determination and are the subject of this brief review.