Biology subjects

Diehl, F. F.

Publications and source records attributed to Diehl, F. F..

3 recordsLinked to original sources

bioRxiv2026

Mechanism of nucleolytic degradation of human ribosomes

Stresses like starvation trigger degradation of mature 40S ribosomes, requiring the coordinated breakdown of large and stable RNA-protein complexes. The atypical kinase RIOK3 orchestrates degradation by binding ubiquitylated 40S ribosomes and promoting rRNA decay. However, the mechanisms and factors that mediate rRNA decay remain unknown. Here we find that in response to starvation, RIOK3 recruits the terminal uridylyl-transferase TUT7 and the exonuclease DIS3L2 to 40S ribosomes. Sequencing analyses show that TUT7 adds oligo(uridine) tails to the 3' end of the 18S rRNA in these ribosomes. DIS3L2 subsequently recognizes uridylated 18S rRNA and carries out 3'-5' decay. We identify major decay intermediates that undergo further uridylation in a process of iterative uridylation and decay. Loss of DIS3L2 impairs 18S rRNA decay during starvation and leads to accumulation of uridylated 18S rRNA. Together these findings define a mechanism for ribosome degradation in which 3' oligo(uridine) tailing drives decay of rRNA from ribosomes.

molecular biology↗

bioRxiv2021

Nucleotide imbalance decouples cell growth from cell proliferation

Nucleotide metabolism supports RNA synthesis and DNA replication to enable cell growth and division. Nucleotide depletion can accordingly inhibit cell growth and proliferation, but how cells sense and respond to changes in the relative levels of individual nucleotides is unclear. Moreover, the nucleotide requirement for biomass production changes over the course of the cell cycle, and how cells coordinate differential nucleotide demands with cell cycle progression is also not well understood. Here we find that excess levels of individual nucleotides can inhibit proliferation by disrupting the relative levels of nucleotide bases needed for DNA replication. The resulting purine and pyrimidine imbalances are not sensed by canonical growth regulatory pathways, causing aberrant biomass production and excessive cell growth despite inhibited proliferation. Instead, cells rely on replication stress signaling to survive during, and recover from, nucleotide imbalance during S phase. In fact, replication stress signaling is activated during unperturbed S phases and promotes nucleotide availability to support DNA replication. Together, these data reveal that imbalanced nucleotide levels are not detected until S phase, rendering cells reliant on replication stress signaling to cope with this metabolic problem, and disrupting the coordination of cell growth and division.

cell biology↗

bioRxiv2020

Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy.

Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 impairing leukemia progression in vivo. RZ-2994 decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers.

cancer biology↗