ATR promotes mTORC1 activity via de novo cholesterol synthesis
DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback. Key mediators of these pathways include ATR and mTORC1, respectively. Previous studies established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. We demonstrate that ATR promotes mTORC1 activity across various human cancer cells and both human and mouse normal cells under basal conditions. This effect is enhanced in human cancer cells (SKMEL28, RPMI-7951, HeLa) following knockdown of p16, a cell cycle inhibitor that we have previously found increases mTORC1 activity and here found increases ATR activity. Mechanistically, ATR promotes de novo cholesterol synthesis and mTORC1 activation through the phosphorylation and upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Interestingly, this pathway is distinct from the regulation of mTORC1 by ATM and may be specific to cancer cells. Finally, ATR-mediated increased cholesterol correlates with enhanced localization of mTOR to lysosomes. Collectively, our findings demonstrate a novel connection linking ATR and mTORC1 signaling through the modulation of cholesterol metabolism.
Authors
- Naveen Kumar Tangudu (ORCID: https://orcid.org/0000-0001-9153-5825)
- Amandine Amalric (ORCID: https://orcid.org/0000-0002-2856-1446)
- Richard Fang (ORCID: https://orcid.org/0009-0001-9559-9735)
- Nadine Hempel (ORCID: https://orcid.org/0000-0002-5574-8783)
- Mai Sun (ORCID: https://orcid.org/0000-0003-0489-1616)
- Apoorva Uboveja (ORCID: https://orcid.org/0000-0002-8037-9676)
- Stacy G. Wendell (ORCID: https://orcid.org/0000-0001-9083-6933)
- Aidan R. Cole (ORCID: https://orcid.org/0000-0001-9647-0848)
- Katherine M. Aird (ORCID: https://orcid.org/0000-0002-5828-2325)
- Zhentai Huang (ORCID: https://orcid.org/0000-0002-8102-464X)
- Matthew L. MacDonald (ORCID: https://orcid.org/0000-0002-2222-2996)
- Raquel Buj (ORCID: https://orcid.org/0000-0002-8355-6666)
- Katarzyna M. Kedziora (ORCID: https://orcid.org/0000-0001-6524-7731)
- Alexander J. Valvezan (ORCID: https://orcid.org/0000-0002-4369-6074)
- Baixue Yang
- Nathaniel W. Snyder (ORCID: https://orcid.org/0000-0001-5643-8747)
- Cassandra Happe
- Alexandra N. Grumet (ORCID: https://orcid.org/0009-0003-8820-4680)
Institutions
- Rutgers, The State University of New Jersey (US)
- University of Pittsburgh (US)
- Johnson University (US)
- Environmental and Occupational Health Sciences Institute (US)
- UPMC Hillman Cancer Center (US)
- University of Pittsburgh Medical Center (US)
- Temple University (US)
- Tsinghua University (CN)
Publication Details
- Journal
- EMBO Reports
- Published
- 2025-06-13
- DOI
- https://doi.org/10.1038/s44319-025-00451-3
- Citations
- 1
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Melanoma Research Foundation
- Ovarian Cancer Research Alliance
- Chan Zuckerberg Initiative
- NIH Office of the Director
- National Cancer Institute
- National Institute of General Medical Sciences
- DOD Peer Reviewed Cancer Research Program