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Endosomal trafficking and DNA damage checkpoint kinases dictate survival to replication stress by regulating amino acid uptake and protein synthesis.

IFOM, The FIRC Institute of Molecular Oncology, Milan 20139, Italy. Electronic address: arta.ajazi@ifom.eu. IFOM, The FIRC Institute of Molecular Oncology, Milan 20139, Italy. Centre for Probe Development and Commercialization, Hamilton, ON L8S 4L8, Canada. Cogentech, S.R.L. Benefit Corporation IT, Milan 20139, Italy. INGM-Fondazione Istituto Nazionale Genetica Molecolare "Romeo and Enrica Invernizzi", Milan 20122, Italy; Department of Biosciences, University of Milan, Milan 20133, Italy. Department of Biosciences, University of Milan, Milan 20133, Italy; Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, Milan 20139, Italy. IFOM, The FIRC Institute of Molecular Oncology, Milan 20139, Italy; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy. IFOM, The FIRC Institute of Molecular Oncology, Milan 20139, Italy; Oncology and Haemato-Oncology Department, University of Milan, Milan 20122, Italy. Electronic address: marco.foiani@ifom.eu.

Developmental cell. 2021;(18):2607-2622.e6
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Abstract

Atg6Beclin 1 mediates autophagy and endosomal trafficking. We investigated how Atg6 influences replication stress. Combining genetic, genomic, metabolomic, and proteomic approaches, we found that the Vps34-Vps15-Atg6Beclin 1-Vps38UVRAG-phosphatydilinositol-3 phosphate (PtdIns(3)P) axis sensitizes cells to replication stress by favoring the degradation of plasma membrane amino acid (AA) transporters via endosomal trafficking and ESCRT proteins, while the PtdIns(3)P phosphatases Ymr1 and Inp53 promote survival to replication stress by reversing this process. An impaired AA uptake triggers activation of Gcn2, which attenuates protein synthesis by phosphorylating eIF2α. Mec1Atr-Rad53Chk1/Chk2 activation during replication stress further hinders translation efficiency by counteracting eIF2α dephosphorylation through Glc7PP1. AA shortage-induced hyperphosphorylation of eIF2α inhibits the synthesis of 65 stress response proteins, thus resulting in cell sensitization to replication stress, while TORC1 promotes cell survival. Our findings reveal an integrated network mediated by endosomal trafficking, translational control pathways, and checkpoint kinases linking AA availability to the response to replication stress.