Biology subjects

Vornbaumen, T.

Publications and source records attributed to Vornbaumen, T..

3 recordsLinked to original sources

bioRxiv2025

Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.

Cellular iron levels must be tightly regulated to ensure sufficient iron for essential enzymatic functions whilst avoiding the harmful generation of toxic species. Here, to better understand how iron levels are controlled, we carry out genome-wide mutagenesis screens in human cells. Alongside mapping known components of iron-sensing, we determine the relative contributions of iron uptake, iron recycling, ferritin breakdown, and mitochondrial flux in controlling the labile iron pool. We also identify SETD2, a histone methyltransferase, as a chromatin modifying enzyme that controls intracellular iron availability through ferritin breakdown. Functionally, we show that SETD2 inhibition or cancer-associated SETD2 mutations render cells iron deficient, thereby driving resistance to ferroptosis, and potentially explaining how some tumours evade anti-tumoural immunity.

cell biology↗

bioRxiv2023

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, its unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H2O2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H2O2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

molecular biology↗

bioRxiv2022

NRF2 activation induces NADH-reductive stress providing a metabolic vulnerability in lung cancer

Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers, however the role of this pathway in cancers with wildtype KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines--an effect that was completely rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.

molecular biology↗