Vps30/Atg6/BECN1 at the crossroads between cell metabolism and DNA damage response. Issue 5 (4th May 2022)

• Record Type: Journal Article
• Authors: Ajazi, Arta; Foiani, Marco
• Is Part Of: Autophagy. Volume 18:Issue 5(2022)
• Page Start: 1202
• Page End: 1204
• Publication Date: 2022-05-04
• Subjects: Amino acids -- Atg6 -- autophagy -- DNA damage -- endosomal trafficking -- Gcn2 -- phosphatidylinositol-3 phosphate -- replication stress -- TORC1; Autophagic vacuoles -- Periodicals; Apoptosis -- Periodicals; Cell death -- Periodicals; Lysosomes -- Periodicals; Degeneration (Pathology) -- Periodicals; Autophagy -- Periodicals; Cell Death -- Periodicals; Lysosomes -- Periodicals; Periodicals; 571.936
• DOI: 10.1080/15548627.2022.2038502
• Languages: English
• ISSNs: 1554-8627

Abstract

ABSTRACT: Several cytotoxic agents used in cancer therapy cause DNA damage and replication stress. Understanding the metabolic determinants of the cell response to replication stress-inducing agents could have relevant implications for cancer treatment. In a recent study, we showed that cell survival during replication stress is influenced by the availability of amino acids, as well as by TORC1 and Gcn2-mediated amino acid sensing pathways. Amino acid starvation, or TORC1 inhibition, sensitizes cells to replication stress conditions, whereas Gcn2 ablation promotes cell survival by stimulating protein synthesis. The Vps34-Vps15-Vps30/Atg6/BECN1-Vps38/UVRAG phosphatidylinositol-3-phosphate (PtdIns3P) complex at the endosomes sets the balance between survival and death signals during replication stress and amino acid starvation. The Vps34-Vps15-Vps30/Atg6/BECN1-Vps38/UVRAG axis promotes the degradation of amino acid transporters, thus sensitizing cells to amino acid starvation, while Vps34-Vps15-Vps30/Atg6/BECN1-Vps38/UVRAG inactivation promotes cell survival by enabling synthesis of stress response proteins mediating survival under replication stress conditions. Our study unravels an autophagy-independent mechanism through which Vps34-Vps30/Atg6/BECN1 promotes lethal events during replication stress.