Biology subjects

Fujimoto, Y.

Publications and source records attributed to Fujimoto, Y..

4 recordsLinked to original sources

bioRxiv2026

CDK12/13 inhibitor, CTX-439, suppresses tumor growth and potentiates BCL-2 family blockade

CDK12 and CDK13 (CDK12/13) regulate transcription by phosphorylating Serine 2 (S2) of the C-terminal domain of RNA polymerase II and have been proposed as therapeutic targets in cancer. Here we report the development of CTX-439, a novel, orally bioavailable, ATP-competitive small-molecule CDK12/13 inhibitor. CTX-439 specifically inhibits S2 phosphorylation and downregulates many genes including those involved in DNA damage repair, thereby exerting a profound anti-cancer effect in vitro and in vivo including breast cancer PDX models. A CRISPR activation screen identified BCL-2 and BCL-xL, anti-apoptotic BCL-2 family members, as genes that when upregulated confer resistance to CTX-439. Simultaneous inhibition of BCL-2/BCL-xL and CDK12/13 rapidly induced apoptosis and significantly suppressed xenograft tumor growth. Mechanistically, CTX-439 downregulates MCL1 protein levels through transcriptional readthrough, shifting cell survival dependency to BCL-2 and BCL-xL. Our study provides novel insights into the anti-tumor effect of CDK12/13 inhibition and proposes a new combination therapy strategy with anti-apoptotic BCL-2 family inhibitors, which may improve therapeutic outcomes in cancer treatment.

cancer biology↗

bioRxiv2026

An anti-aggregation region of the SGS3 N-terminal IDR is essential for secondary siRNA biogenesis

Secondary siRNA biogenesis amplifies small RNA signals from target transcripts and plays a pivotal role in plant development and defense responses. The RNA-binding protein SGS3 is essential for this pathway, recruiting RNA-dependent RNA polymerase 6 (RDR6) to Argonaute-small RNA-bound targets. The N-terminal intrinsically disordered region (IDR) of SGS3, which contains a prion-like domain (PrLD), has been reported to drive liquid-liquid phase separation, forming siRNA bodies, and to be required for secondary siRNA production. However, the molecular mechanism by which the N-terminal IDR contributes to secondary siRNA production remains unclear. Here, using in vitro reconstitution and in planta assays, we show that the N-terminal IDR comprises two functional modules: the PrLD and a negatively charged region (NCR). The PrLD is required for phase separation and siRNA body formation but is dispensable for secondary siRNA production. In contrast, mutations in the NCR caused SGS3 to form abnormally large cytoplasmic assemblies and markedly impaired secondary siRNA production. These results suggest that the N-terminal IDR helps maintain SGS3 in a functional, soluble state that supports efficient secondary siRNA biogenesis.

molecular biology↗

bioRxiv2025

Noradrenergic efferent subsystems that gate traumatic social learning

Individuals experience varying magnitudes of stress in their daily lives. Although stress responses facilitate adaptive processes to cope with changing environments, severe stress can lead to traumatic learning and anxiety disorders. However, the neuronal mechanisms underlying the influence of stress severity on these processes remain unclear. Here, we show that traumatic social stress engages anatomically distinct locus coeruleus noradrenergic (LCNA) subpopulations that exhibit dynamic responses scaled to aversive salience. Using whole-brain activity and axonal projection mappings, we identified projectome subtypes of LCNA neurons, which are differentially recruited by single versus consecutive aversive social experiences. While hippocampus-projecting LCNA neurons responded to general social contacts, thalamus-projecting LCNA neurons tracked the aversive salience of social stimuli. Functional manipulations revealed a bidirectional role of thalamus-projecting LCNA neurons in social avoidance learning. These findings reveal the functional architecture of LCNA subsystems that regulate traumatic social learning via dynamic scaling to aversive salience.

neuroscience↗

bioRxiv2021

Short 5'UTR enables optimal translation of plant virus tricistronic RNA via leaky scanning

Regardless of the general model of translation in eukaryotic cells, a number of studies suggested that many of mRNAs encode multiple proteins. Leaky scanning, which supplies ribosomes to downstream open reading frames (ORFs) by read-through of upstream ORFs, is the most major regulatory mechanism to translate polycistronic mRNAs. However, the general regulatory factors controlling leaky scanning and their biological relevance have rarely been elucidated, with exceptions such as the Kozak sequence. Here, we have analyzed the strategy of a plant RNA virus to translate three movement proteins from a single RNA molecule through leaky scanning. The in planta and in vitro results indicate that significantly shorter 5' UTR of the most upstream ORF promotes leaky scanning, potentially finetuning the translation efficiency of the three proteins in a single RNA molecule to optimize viral propagation. Moreover, in plant endogenous mRNAs, we found that shorter UTRs were more frequently observed in uORFs of polycistronic mRNAs. We propose that the promotion of leaky scanning induced by a short 5' UTR (LISH), together with the Kozak sequence, is a conserved gene regulation mechanism not only in viruses but also in eukaryotes.

plant biology↗