Biology subjects

Ding, H.-F.

Publications and source records attributed to Ding, H.-F..

3 recordsLinked to original sources

bioRxiv2025

The mevalonate pathway couples lipid metabolism to amino acid synthesis via ubiquinone-dependent redox control

The mevalonate pathway produces sterols and isoprenoids that support cancer cell growth, yet its broader metabolic functions remain incompletely defined. Here, we show that this pathway sustains amino acid biosynthesis by promoting mitochondrial NAD regeneration through ubiquinone-dependent electron transport. Statin-mediated inhibition of the mevalonate pathway impairs oxidative phosphorylation, lowers the NAD/NADH ratio, and suppresses de novo serine and aspartate synthesis, thereby activating the GCN2-eIF2-ATF4 amino acid deprivation response. The resulting depletion of serine-derived glycine and one-carbon units, together with reduced aspartate availability, limits purine and pyrimidine nucleotide production. Expression of the bacterial NADH oxidase LbNOX or the alternative oxidase AOX restores NAD levels and rescues statin-induced growth inhibition. These findings suggest that impaired NAD regeneration is a key mechanism contributing to the anti-proliferative activity of statins, linking the mevalonate pathway to mitochondrial electron transport- dependent control of amino acid metabolism. SignificanceThis study identifies the mevalonate pathway as a regulator of amino acid biosynthesis through mitochondrial electron transport-dependent NAD regeneration and reveals redox disruption as a key mechanism contributing to the anti-proliferative effects of statins.

cancer biology↗

bioRxiv2024

DKC1-mediated pseudouridylation of rRNA targets hnRNP A1 to sustain IRES-dependent translation and ATF4-driven metabolic adaptation

The pseudouridine synthase DKC1 regulates internal ribosome entry site (IRES)-dependent translation and is upregulated in cancers by the MYC family of oncogenic transcription factors. We investigated the functional significance of DKC1 in MYCN-amplified neuroblastoma and its underlying mechanisms. A key function of DKC1 is to promote an ATF4-mediated gene expression program for amino acid metabolism and stress adaptation. We identified hnRNP A1, an IRES trans-acting factor, as a critical downstream mediator of DKC1 in sustaining ATF4 expression and IRES-dependent translation. We found that DKC1-mediated pseudouridylation at two specific 28S rRNA sites is essential for maintaining hnRNP A1 protein expression. Moreover, hnRNP A1 interacts with and stabilizes ATF4 mRNA, significantly increasing the protein expression of the ATF4 V1 variant, which contains an IRES element in its mRNA. Additionally, we found that cellular stress induces hnRNP A1, which is required for ATF4 induction under such conditions. Collectively, our study reveals a MYC-activated DKC1-hnRNP A1 axis that drives ATF4-mediated metabolic adaptation, supporting cancer cell survival under metabolic stress during cancer development.

cancer biology↗

bioRxiv2024

Transcriptome-wide quantitative profiling of PUS7-dependent pseudouridylation by nanopore direct long read RNA sequencing

Understanding the interactions between different RNA modifications is essential for unraveling their biological functions. Here, we report NanoPsiPy, a computational pipeline that employs nanopore direct RNA sequencing to identify pseudouridine ({Psi}) sites and quantify their levels at single-nucleotide resolution. We validated NanoPsiPy by transcriptome-wide profiling of PUS7-dependent {Psi} sites in poly-A RNA and rRNA. NanoPsiPy leverages {Psi}-induced U-to-C basecalling errors in nanopore sequencing data, allowing detection of both low and high stoichiometric {Psi} sites. We identified 8,624 PUS7-dependent {Psi} sites in 1,246 mRNAs encoding proteins associated with ribosome biogenesis, translation, and energy metabolism. Importantly, integrative analysis revealed that PUS7 knockdown increases global mRNA N6-methyladenosine (m6A) and 5-methylcytosine (m5C) levels, suggesting an antagonistic relationship between {Psi} and these modifications. Our study underscores the potential of nanopore direct RNA sequencing in revealing the co-regulation of RNA modifications and the capacity of NanoPsiPy in analyzing pseudouridylation and its impact on other RNA modifications.

cancer biology↗