Concerted 2-5A-Mediated mRNA Decay and Transcription Reprogram Protein Synthesis in the dsRNA Response.

Viral and endogenous double-stranded RNA (dsRNA) is a potent trigger for programmed RNA degradation by the 2-5A/RNase L complex in cells of all mammals. This 2-5A-mediated decay (2-5AMD) is a conserved stress response switching global protein synthesis from homeostasis to production of interferons (IFNs). To understand this mechanism, we examined 2-5AMD in human cells and found that it triggers polysome collapse characteristic of inhibited translation initiation. We determined that translation initiation complexes and ribosomes purified from translation-arrested cells remain functional. However, spike-in RNA sequencing (RNA-seq) revealed cell-wide decay of basal mRNAs accompanied by rapid accumulation of mRNAs encoding innate immune proteins. Our data attribute this 2-5AMD evasion to better stability of defense mRNAs and positive feedback in the IFN response amplified by RNase L-resistant molecules. We conclude that 2-5AMD and transcription act in concert to refill mammalian cells with defense mRNAs, thereby "prioritizing" the synthesis of innate immune proteins.

Real-time 2-5A kinetics suggest that interferons ß and λ evade global arrest of translation by RNase L.

Cells of all mammals recognize double-stranded RNA (dsRNA) as a foreign material. In response, they release interferons (IFNs) and activate a ubiquitously expressed pseudokinase/endoribonuclease RNase L. RNase L executes regulated RNA decay and halts global translation. Here, we developed a biosensor for 2',5'-oligoadenylate (2-5A), the natural activator of RNase L. Using this biosensor, we found that 2-5A was acutely synthesized by cells in response to dsRNA sensing, which immediately triggered cellular RNA cleavage by RNase L and arrested host protein synthesis. However, translation-arrested cells still transcribed IFN-stimulated genes and secreted IFNs of types I and III (IFN-ß and IFN-λ). Our data suggest that IFNs escape from the action of RNase L on translation. We propose that the 2-5A/RNase L pathway serves to rapidly and accurately suppress basal protein synthesis, preserving privileged production of defense proteins of the innate immune system.

Novel Cancer Prevention Strategies in Individuals With Hereditary Cancer Syndromes: Focus on BRCA1, BRCA2, and Lynch Syndrome.

Germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes confer elevated risks of breast, ovarian, and other cancers. Lynch syndrome (LS) is associated with increased risks of multiple cancer types including colorectal and uterine cancers. Current cancer risk mitigation strategies have focused on pharmacologic risk reduction, enhanced surveillance, and preventive surgeries. While these approaches can be effective, they stand to be improved on because of either limited efficacy or undesirable impact on quality of life. The current review summarizes ongoing investigational efforts in cancer risk prevention strategies for patients with germline PVs in BRCA1, BRCA2, or LS-associated genes. These efforts span radiation, surgery, and pharmacology including vaccine strategies. Understanding the molecular events involved in the premalignant to malignant transformation in high-risk individuals may ultimately contribute significantly to novel prevention strategies.

Comprehensive Diagnosis and Management of Malignant Bowel Obstruction: A Review.

Malignant bowel obstruction is a common complication of advanced gastrointestinal, gynecologic, and genitourinary tumors. Patients present with nausea, vomiting, abdominal pain, and constipation. Cross-sectional imaging is essential to make a diagnosis of bowel obstruction. Initial management is conservative with fluid replacement, electrolyte replacement, bowel rest and sometimes nasogastric decompression. Numerous advanced options exist for definitive management, though none are overly promising but nevertheless may improve quality and quantity of life. Surgical bypass, endoscopic stenting, and endoscopic decompression are some of the options with variable efficacy and are employed in select patients. Chemotherapy may be utilized if the bowel obstruction resolves to reduce tumor burden in a limited number of patients. Parenteral nutrition is an option and should typically be used in surgical patients with good functional and nutritional status with limited tumor burden or curative intent. Palliative care and hospice should be discussed in patients with advanced malignancy who present with peritoneal carcinomatosis or multiple levels of obstruction. Overall prognosis of malignant bowel obstruction is poor, and median survival ranges from 26 to 192 days.