Vps30/Atg6/BECN1 at the crossroads between cell metabolism and DNA damage response.

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.

• Authors: Arta Ajazi, Marco Foiani
• Journal: Autophagy (Autophagy) Vol. 18 Issue 5 Pg. 1202-1204 (05 2022) ISSN: 1554-8635 [Electronic] United States
• PMID: 35167420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Autophagy-Related Proteins
• Beclin-1
• Mechanistic Target of Rapamycin Complex 1

Topics

• Amino Acids
• Autophagy (physiology)
• Autophagy-Related Proteins
• Beclin-1
• DNA Damage
• Mechanistic Target of Rapamycin Complex 1