Author Correction: Structural basis of tRNA recognition by the m3C RNA methyltransferase METTL6 in complex with SerRS seryl-tRNA synthetase
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Chemical reactivity of RNA and its modifications with hydrazine
RNA modifications are essential for the regulation of cellular processes and have a key role in diseases such as cancer and neurological disorders. A major challenge in the analysis of RNA modification is the differentiation between isomers, including methylated nucleosides as well as uridine and pseudouridine. A solution is their differential chemical reactivity which enables isomer discrimination by mass spectrometry (MS) or sequencing. In this study, we systematically determine the chemical reactivity of hydrazine with RNA and its native modifications in an aniline-free environment. We optimize the conditions to achieve nearly full conversion of all uridines while avoiding RNA cleavage. We apply the conditions to native tRNAPhe which allows discrimination of pseudouridine and uridine by MALDI-MS. Furthermore, we determine the identity of the reaction product of hydrazine with various modified nucleosides using high resolution mass spectrometry and quantify the reaction yield in native tRNA from E. coli and human cells under various hydrazine conditions. Most modified nucleosides react quantitatively at lower hydrazine concentration while uridines do not decompose under these conditions. Thus, this study paves the way to exploit aniline-free hydrazine reactions in the detection of RNA modifications through MS and potentially even long-read RNA sequencing.
Mechanistic basis for PYROXD1-mediated protection of the human tRNA ligase complex against oxidative inactivation
The metazoan tRNA ligase complex (tRNA-LC) has essential roles in tRNA biogenesis and unfolded protein response. Its catalytic subunit RTCB contains a conserved active-site cysteine that is susceptible to metal ion-induced oxidative inactivation. The flavin-containing oxidoreductase PYROXD1 preserves the activity of human tRNA-LC in a NAD(P)H-dependent manner, but its protective mechanism remains elusive. Here, we report a cryogenic electron microscopic structure of the human RTCB–PYROXD1 complex, revealing that PYROXD1 directly interacts with the catalytic center of RTCB through its carboxy-terminal tail. NAD(P)H binding and FAD reduction allosterically control PYROXD1 activity and RTCB recruitment, while reoxidation of PYROXD1 enables timed release of RTCB. PYROXD1 interaction is mutually exclusive with Archease-mediated RTCB guanylylation, and guanylylated RTCB is intrinsically protected from oxidative inactivation. Together, these findings provide a mechanistic framework for the protective function of PYROXD1 that maintains the activity of the tRNA-LC under aerobic conditions.
Interracial contact shapes racial bias in the learning of person-knowledge
During impression formation, perceptual cues facilitate social categorization while person-knowledge can promote individuation and enhance person memory. Although there is extensive literature on the cross-race recognition deficit, observed when racial ingroup faces are recognized more than outgroup faces, it is unclear whether a similar deficit exists when recalling individuating information about outgroup members. To better understand how perceived race can bias person memory, the present study examined how self-identified White perceivers’ interracial contact impacts learning of perceptual cues and person-knowledge about perceived Black and White others over five sessions of training. While person-knowledge facilitated face recognition accuracy for low-contact perceivers, face recognition accuracy did not differ for high-contact perceivers based on person-knowledge availability. The results indicate a bias towards better recall of ingroup person knowledge, which decreased for high-contact perceivers across the five-day training but simultaneously increased for low-contact perceivers. Overall, the elimination of racial bias in recall of person-knowledge among high-contact perceivers amid a persistent cross-race deficit in face recognition suggests that contact may have a greater impact on the recall of person-knowledge than on face recognition.
A microscale thermophoresis-based enzymatic RNA methyltransferase assay enables the discovery of DNMT2 inhibitors
RNA methyltransferases (MTases) have recently become increasingly important in drug discovery. Yet, most frequently utilized RNA MTase assays are limited in their throughput and hamper this rapidly evolving field of medicinal chemistry. This study developed a microscale thermophoresis (MST)-based split aptamer assay for enzymatic MTase investigations, improving current methodologies by offering a non-proprietary, cost-effective, and highly sensitive approach. Our findings demonstrate the assay’s effectiveness across different RNA MTases, including inhibitor characterization of METTL3/14, DNMT2, NSUN2, and S. aureus TrmD, enabling future drug discovery efforts. Using this concept, a pilot screening on the cancer drug target DNMT2 discovered several hit compounds with micromolar potency.
In vivo surface-enhanced Raman scattering techniques: nanoprobes, instrumentation, and applications
Surface-enhanced Raman scattering (SERS) has emerged as a powerful tool in various biomedical applications, including in vivo imaging, diagnostics, and therapy, largely due to the development of near-infrared (NIR) active SERS substrates. This review provides a comprehensive overview of SERS-based applications in vivo, focusing on key aspects such as the design considerations for SERS nanoprobes and advancements in instrumentation. Topics covered include the development of NIR SERS substrates, Raman label compounds (RLCs), protective coatings, and the conjugation of bioligands for targeted imaging and therapy. The review also discusses microscope-based configurations such as scanning, widefield imaging, and fiber-optic setups. Recent advances in using SERS nanoprobes for in vivo sensing, diagnostics, biomolecule screening, multiplex imaging, intraoperative guidance, and multifunctional cancer therapy are highlighted. The review concludes by addressing challenges in the clinical translation of SERS nanoprobes and outlines future directions, emphasizing opportunities for advancing biomedical research and clinical applications.
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