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These m 5C additions are recognized by ALYREF, initiating nuclear mRNA export. m 5C formation in mRNAs is mainly catalyzed by the RNA methyltransferase NOP2/Sun RNA Methyltransferase 2 (NSUN2). 5-methylcytosine (m 5C) additions to RNAs display a crucial modification of RNAs important for nuclear export. ALYREF has been demonstrated to mainly bind to the 5’ and 3’ ends of mRNA in vivo to facilitate this nuclear export. As part of the nuclear export TREX complex, ALYREF acts as an mRNA export adaptor by mediating the interaction between the mRNA and the mRNA export receptor nuclear RNA export factor 1 (NXF1).
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The RNA-binding protein ALYREF (also called THOC4) was originally discovered as a partner of the TRanscription EXport (TREX) protein complex that binds to spliced mRNAs and enables transfer to the cytoplasm. Thus, a more profound understanding of the molecular mechanisms involved in TNBC formation is of paramount importance to improve the clinical outcome of those patients and ensure the development of novel and more effective cancer treatments. Though the majority of patients receive cytotoxic chemotherapy, progress in understanding the underlying biology of TNBC has led to the introduction of poly(ADP-ribose) polymerase (PARP) inhibitors, Trop-2 directed antibody drug conjugates and immune checkpoint inhibitors in certain patient cohorts. Triple-negative breast cancer (TNBC, i.e., negative for estrogen receptor, progesterone receptor and HER2 protein) is the most aggressive breast cancer subtype, with poor prognosis due to limited therapeutic options. In general, breast cancer is a very heterogeneous disease in terms of underlying biology, treatment response and prognosis, and it is commonly classified into several subtypes based on gene expression profiles or simplified into three major subtypes based on the presence or absence of immunohistochemical markers. Approximately 276,480 cases of female breast cancer were expected to be diagnosed in the United States in 2020, and breast cancer alone is estimated to account for 30% of all new cancer diagnoses in women. Overall, our study describes ALYREF as a novel factor contributing to breast carcinogenesis and identifies novel molecular mechanisms of regulation the two isoforms of NEAT1.īreast cancer is the leading cause of cancer-related deaths in women aged 20–60 years. Importantly, by stabilizing CPSF6, a protein that selectively activates the post-transcriptional generation of the short isoform of NEAT1, as well as by direct binding and stabilization of the short isoform of NEAT1, ALYREF selectively fine-tunes the expression of the short NEAT1 isoform.
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Mechanistically, we found that ALYREF binds to the NEAT1 promoter region to enhance the global NEAT1 transcriptional activity. Transcriptional profiling, phenocopy and rescue experiments identified the short isoform of the lncRNA NEAT1 as a molecular trigger for ALYREF effects in breast cancer.
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ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown.