Biology subjects

Soulet, C.

Publications and source records attributed to Soulet, C..

5 recordsLinked to original sources

bioRxiv2026

The DNA Damage Response kinase ATM restricts Golgi extension

The master kinases of the DNA damage response (DDR), ATR, ATM and DNA-PK, become active in response to DNA damage and orchestrate a downstream wave of phosphorylations contributing to DNA damage repair and preservation of cellular homeostasis. Of them, we recently demonstrated that ATM binds the pool of the lipid phosphatidyl-inositol-4-phosphate (PI4P) situated at the Golgi membrane. Depending on PI4P availability at Golgi membranes, ATM is more or less titrated away from the nucleus, which translates into responses to nuclear DNA damage of matching intensity. Building on this knowledge, in this work we asked if, beyond the Golgi merely serving as a docking platform that retains ATM away from the nucleus, ATM does exert any role important for Golgi biology. We found that ATM maintains Golgi morphology by counteracting its excessive deployment. This occurs both by its mere presence (likely antagonizing the Golgi-stretching action of the protein GOLPH3) and by phosphorylating Golgi-resident substrates. Of relevance, we also report that the morphological alterations caused to the Golgi without ATM affect the biology of a model Golgi cargo. Our findings nourish the growing evidence that kinases of ATMs family display functional interactions with membranes and highlights an underappreciated crosstalk between the Golgi and the nucleus.

cell biology↗

bioRxiv2024

SARS-CoV-2 predation of Golgi-bound PI4P primes the massive activation of the DNA Damage Response kinase ATM in the cytoplasm

Like all viruses, SARS-CoV-2, the causative agent of COVID-19, relies on host cell resources to replicate. Our study reveals that, among these resources, SARS-CoV-2 hijacks the oxysterol-binding protein 1 (OSBP1) transporter to exploit the Golgi-bound phosphatidylinositol-4-phosphate (PI4P) pool. This leads to a depletion of Golgi-resident PI4P, triggering the activation of the ATM DNA Damage Response (DDR) kinase in the cytoplasm. As such, ATM, typically anchored to PI4P at the Golgi in an inactive state, undergoes auto-phosphorylation and cytoplasmic release upon SARS-CoV-2-induced PI4P depletion. Conversely, pharmacological inhibition of ATM auto-phosphorylation, which stabilizes its interaction with PI4P, significantly impairs SARS-CoV-2 replication. The requirement for PI4P and impact of ATM inhibition might be conserved across coronaviruses, as similar effects were observed with HCoV-229E. Finally, SARS-CoV-2-induced, cytoplasmic ATM pre-activation primes cells for an accelerated response to DNA damage, which might contribute to the severe outcomes of COVID-19 observed in cancer patients undergoing chemo- or radiotherapy. Therefore, this study uncovers a DNA damage-independent mode of ATM activation and highlights the potential of ATM inhibitors as therapeutic agents against COVID-19.

microbiology↗

bioRxiv2024

Neutral lipids restrict the mobility of broken DNA molecules during comet assays

One widespread technique to assess in relative terms the amount of broken DNA present in the genome of individual cells consists in immobilizing the cells nucleus under an agarose pad (called the nucleoid) and subject the whole genome to electrophoresis to force broken DNA molecules out of it. Since the migrating DNA molecules create a tail behind the nucleoid, this technique is named the comet assay. While performing comet assays regularly, we systematically observed circular regions devoid of DNA within the nucleoid region. We characterize here that these correspond to clusters of neutral (apolar) lipids, since they could be labelled with neutral lipid-dying molecules, increased when cells were fed with oleic acid, and were irresponsive to the electrophoretic field. Of relevance, de-lipidation assays either in vivo, or in vitro, show that these neutral lipids within the nucleoid limit the ability of broken DNA molecules to migrate into the comet tail. From a technical point of view, we show that de-lipidation permits a wider range for the detection of broken DNA molecules. Biologically, we put forward the notion that neutral lipids in contact with DNA may locally exert regulatory functions within the cells nucleus.

cell biology↗

bioRxiv2022

A Sterol-PI(4)P exchanger controls the Tel1/ATM axis of the DNA Damage Response

Upon DNA damage, cells activate the DNA Damage Response (DDR) to coordinate proliferation and DNA repair. Dietary, metabolic, and environmental inputs are emerging as modulators of how DNA surveillance and repair take place. Lipids hold potential to convey these cues, although little is known about how. We observed that lipid droplet (LD) number specifically increased in response to DNA breaks. We show that the selective storage of sterols into these LD concomitantly stabilizes phosphatidyl-4-inositol (PI(4)P) at the Golgi, where it binds the DDR kinase ATM. In turn, this titration attenuates the initial nuclear ATM-driven response to DNA breaks, thus allowing processive repair. Further, manipulating this loop impacts the kinetics of DNA damage signaling and repair in a predictable manner. Thus, our findings have major implications for tackling genetic instability pathologies through dietary and pharmacological interventions.

cell biology↗

bioRxiv2021

Negative curvature-promoting lipids instruct nuclear ingression of low autophagic potential vacuoles

Membrane contact sites are functional nodes at which organelles exchange information through moving ions, proteins and lipids, thus driving the reorganization of metabolic pathways and the adaptation to changing cues. The nuclear-vacuole junction of Saccharomyces cerevisiae is among the most extensive and better-known organelle contact sites, described to expand in response to various metabolic stresses. While using genotoxins with unrelated purposes, we serendipitously discovered a phenomenon that we describe as the most extreme and intimate contact ever reported between nuclei and vacuoles: the vacuole becomes completely internalized in the nucleus. We define lipids supporting negative curvature, such as phosphatidic acid and sterols, as bona-fide drivers of this event. Functionally, we purport that internalized vacuoles are low efficiency ones whose removal from the cytoplasm optimizes cargo interaction with functional vacuoles. Thus, our findings also point to nucleus-vacuole interactions as important for metabolic adaptation. Yet, rather than by inter-organelle exchanges, the underlying mechanism literally concurs with vacuolar sequestration.

cell biology↗