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PNAS Papers on Meiotic Crossover, RNA Targeting, SNAT7 mTORC1 Regulation

A Stanford University-led team looks at meiotic crossover formation and chromosome segregation in a Caenorhabditis elegans worm model. With the help of CRISPR genome editing, immunofluorescence imaging, and other experiments, the team saw signs that crossover formations in C. elegans are bolstered by cyclin-dependent kinase 2 (CDK-2) binding to a cyclin-like protein called COSA-1, along with CDK-2 activation of the crossover-related MutS-gamma complex via MSH-5 phosphorylation. Together, the authors say, their results "support a model in which robustness of crossover designation reflects a positive feedback mechanism involving CDK-2-mediated phosphorylation and scaffold-like properties of the MSH5 C-terminal tail, features that combine to promote full recruitment and activity of crossover-promoting complexes."

Investigators at the University of North Carolina at Chapel Hill, New York University, and the University of Sherbrooke outline a strategy for focusing in on candidate small molecules for targeting and modifying RNA activity. "The transcriptome represents an attractive but underused set of targets for small-molecule ligands," they explain, noting that they developed "a technology that leverages fragment-based screening and SHAPE-MaP RNA structure probing to discover small-molecule fragments that bind an RNA structure of interest." With this approach, the team first found thiamine pyrophosphate (TPP) riboswitch-binding fragments before tapping into structure-activity clues to come up with a high affinity TPP riboswitch-binding linked-fragment ligand capable of tweaking RNA conformation.

A University of Texas Southwestern Medical Center team describes a role for the lysosomal glutamine and asparagine transporter SNAT7 in regulating the mammalian target of rapamycin complex 1 (mTORC1) — a nutrient and cell growth-related signaling pathway upended in some human cancers, metabolic conditions, or diabetes cases. With protein interaction experiments and other approaches, the investigators assessed cell lines missing Rag proteins that mediate some amino acid interactions with mTORC1, ultimately flagging SNAT7 as a mediator between glutamine and asparagine signaling and mTORC1 activity. SNAT7 also appeared to be essential for the growth of pancreatic cancer cells with KRAS driver mutations, they report, acting through a pathway that activates mTORC1 with the help of micropinocytosis transport. "We identify SNAT7 as an important regulator of mTORC1," the authors write. "We believe this research will provide valuable insight about mTORC1 biology and may uncover novel therapeutic targets for patients."

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