Biology subjects

Roumelioti, G.

Publications and source records attributed to Roumelioti, G..

2 recordsLinked to original sources

bioRxiv2025

Wee1 opposes APC/C(Cdh1) activity to promote S-phase entry

Wee1 phosphorylates and inhibits CDK activity to inhibit mitotic entry and establish a G2 DNA damage checkpoint. Consequently, Wee1 inhibitors are in clinical trials, developed to be synthetically lethal in TP53 mutant tumours that become reliant on a Wee1-mediated DNA damage checkpoint. However, Wee1 inhibitors have efficacy in TP53 wild-type tumours and many trials have been terminated due to high levels of toxic side-effects, suggesting that Wee1 has unknown functions. Here, we show that Wee1 promotes cell cycle re-entry from quiescence (G0) by opposing the activity of the E3 ubiquitin ligase, APC/CCdh1. Wee1 phosphorylates Cdh1 (FZR1) at key residues that mediate the interaction between Cdh1 and APC/C. Cells with loss-of-function of Wee1 during G0/G1 have delayed S-phase entry, an impaired G1/S transition, abnormal S-phase accumulation of the CDK inhibitor p21 and enter a p21-dependent G2 arrest. Reduced expression of APC/CCdh1 or p21 renders cells more sensitive to acute Wee1 inhibition and both pathways are downregulated in acquired Wee1 inhibitor resistance. Our study reveals a new cell cycle control mechanism that has implications for how Wee1 inhibitors should be used in the clinic.

cell biology↗

bioRxiv2021

EROS-mediated control of NOX2 and P2X7 biosynthesis

EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase (OST) machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions and P2X7 is almost absent in EROS deficient mouse and human primary cells. Accordingly, lack of EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation and possibly gene therapy.

immunology↗