Lim, S.-T. S. | bioRxiv Science

bioRxiv2026

SON-mediated circular RNA suppression promotes PKR signaling and radiation resistance in glioblastoma

Glioblastoma (GBM) exhibits extensive loss of circular RNAs (circRNAs), yet the mechanisms driving this depletion and its functional consequences remain unclear. Here, we identify the splicing co-factor SON as a previously unrecognized suppressor of circRNA biogenesis in GBM. CircRNA sequencing revealed widespread increases in circRNA abundance following SON knockdown. Conversely, elevated SON expression in GBM, with further increases in radiation-resistant models, was associated with widespread circRNA loss, including reduced expression of circUSP1 and circSUCO. SON knockdown increased circRNA abundance and attenuated activation of the dsRNA-responsive kinase PKR and downstream NF{kappa}B signaling, whereas radiation-resistant GBM cells exhibited enhanced PKR/NF{kappa}B activation that was attenuated by SON depletion. Importantly, overexpression of the SON-suppressed circRNAs circUSP1 and circSUCO reduced PKR activation and selectively decreased clonogenic survival following irradiation in radiation-resistant GBM cells, with little effect on parental cells. Together, these findings identify a previously unrecognized SON/circRNA/PKR regulatory pathway linking RNA processing to acquired radiation resistance in GBM and highlight specific PKR-inhibitory circRNAs as potential therapeutic tools for resensitizing radiation-resistant GBM to radiotherapy.

cancer biology↗

bioRxiv2023

A mouse model of ZTTK syndrome reveals indispensable SON functions in organ development and hematopoiesis

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss-of-function of SON. While ZTTK syndrome patients suffer from numerous symptoms, the lack of model organisms hamper our understanding of both SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/-) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son+/- mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. Furthermore, we identified hematopoietic abnormalities in Son+/- mice, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency inclines cell fate toward the myeloid lineage but compromises lymphoid lineage development by reducing key genes required for lymphoid and B cell lineage specification. Additionally, Son haploinsufficiency causes inappropriate activation of erythroid genes and impaired erythroid maturation. These findings highlight the importance of the full gene dosage of Son in organ development and hematopoiesis. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.

genetics↗