Biology subjects

Cakil, O.

Publications and source records attributed to Cakil, O..

3 recordsLinked to original sources

bioRxiv2026

The DGKK mRNA is a primary target of the Prader-Willi syndrome-associated snoRNA SNORD116

Box C/D small nucleolar RNAs (SNORDs) classically guide site-specific modification of ribosomal RNAs through antisense elements located upstream of their D[prime] and D boxes, termed ASE1 and ASE2. Yet many orphan SNORDs have no established primary targets, including the paternally expressed multicopy SNORD116 family implicated in Prader-Willi syndrome. Our previous comparative analysis identified the DGKK/Dgkk interaction as the most evolutionarily persistent candidate involving the highly conserved SNORD116 ASE1 sequence and showed that SNORD116 depletion increases DGKK RNA abundance in human cells. Here, we re-evaluated this interaction alongside a focused set of recently published candidates and asked whether evolutionary persistence was accompanied by independent evidence of regulation. DGKK/Dgkk showed reproducible increases following transient SNORD116 loss across human iPSC-derived neural cells and in brain tissues from Snord116-knockout mice. Its predicted SNORD116 interaction site combined a marked local depletion of human sequence variation with an overlapping cis-regulatory interval identified in mouse. SNORD116 deficiency was also associated with increased endogenous DGK[kappa]; protein across several mouse brain regions, including the hypothalamus. More broadly, comparison across the candidate set showed that evolutionary persistence, duplex stability and expression response did not systematically align, indicating that sequence-based properties alone do not allow reliable prediction of responses to SNORD116 loss. Together, these data support DGKK/Dgkk as the best-supported primary regulatory target of SNORD116 to date and establish it as a model for dissecting the regulatory mechanism of this orphan snoRNA family.

molecular biology↗

bioRxiv2026

FMRP controls diacylglycerol-dependent neuronal activity by mediating m6A-regulated translation efficiency

Fragile X syndrome (FXS), a leading inherited cause of intellectual developmental disorder and autism, results from loss of the RNA-binding protein FMRP. Loss of FMRP causes excessive neuronal protein synthesis contributing to widespread functional disturbances, yet the mechanisms linking FMRP to specific mRNA targets remain unclear. We show that FMRP promotes translation of the brain mRNA DGK{kappa} by binding mA-modified repetitive RNA motifs, thereby relieving a translational block encoded within its sequence. FMRP loss sharply reduces neuronal DGK{kappa}, and DGK{kappa} depletion alone reproduces hallmark FXS phenotypes, including hyperactivity, compulsive behavior, overgrowth, dendritic spine abnormalities, overactivated diacylglycerol signaling and increased protein synthesis. These findings identify DGK{kappa} as a key effector of FMRP function and establish a regulatory axis where mA RNA modification modulates neuronal translation. This work defines new principles of translational control in neurodevelopmental disorders and positions DGK{kappa} as a central driver of FXS pathogenesis.

molecular biology↗

bioRxiv2021

AAV-delivery of diacylglycerol kinase kappa achieves long-term rescue of Fmr1-KO mouse model deficits of fragile X syndrome

Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. It results from the lack of the RNA binding protein FMRP and is associated with the overactivation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk) is a main mRNA target of FMRP in cortical neurons. Here we show that diacylglycerol kinase kappa (DGKk), when modified as to become FMRP-independent and delivered into the brain of adolescent mice using adeno-associated viral vectors, corrects brain diacylglycerol and phosphatidic acid homeostasis and the main phenotypic behaviors of the Fmr1-KO mouse model of FXS. Thus, DGKk appears as a key triggering factor of FXS pathomechanism while providing a possible means of intervention for FXS gene therapy. One sentence summaryDGKk gene therapy in Fmr1-KO mouse model

neuroscience↗