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Cited by 5PI3K/AKT/mTOR signaling in cancerCancer, Lipids, and MetabolismProtein Kinase Regulation and GTPase Signaling

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ATR promotes mTORC1 activity via de novo cholesterol synthesis

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Tangudu, Naveen Kumar, Grumet, Alexandra N, Fang, Richard, Buj, Raquel, Cole, Aidan R, Uboveja, Apoorva, Amalric, Amandine, Yang, Baixue, Huang, Zhentai, Happe, Cassandra, Sun, Mai, Gelhaus, Stacy L, MacDonald, Matthew L, Hempel, Nadine, Snyder, Nathaniel W, Kedziora, Katarzyna M, Valvezan, Alexander J, Aird, Katherine M·2025·EMBO Reports
DOI 10.1038/s44319-025-00451-3PMC PMC12287318

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Abstract

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.

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Metadata

Authors
Tangudu, N. K., Grumet, A. N., Fang, R., Buj, R., Cole, A. R., Uboveja, A., Amalric, A., Yang, B., Huang, Z., Happe, C., Sun, M., Gelhaus, S. L., MacDonald, M. L., Hempel, N., Snyder, N. W., Kedziora, K. M., Valvezan, A. J., & Aird, K. M.
Affiliations
  • University of Pittsburgh (US)
  • Rutgers Cancer Institute (US)
  • Temple University (US)
Corresponding author
  • Valvezan, Alexander J
  • Aird, Katherine M
ORCID
Venue
EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2025-06-13
Volume
26
Issue
14
Pages
3574-3593
ISSN
  • 1469-221X (ISSN-L)
  • 1469-3178
DOI
10.1038/s44319-025-00451-3
PMC
PMC12287318
OpenAlex
W4411281801
Cited by
5
References
3
Citations by year
2026: 1 · 2025: 3
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • HHS | NIH | National Cancer Institute (R37CA240625, R01CA259111, P30CA047904)
  • HHS | NIH | National Institute of General Medical Sciences (R35GM155379, T32GM133332)
  • HHS | NIH | NIH Office of the Director (S10OD023402, S10OD032141)
  • DOD | MHS | CDMRP | DOD Peer Reviewed Cancer Research Program (HT9425-23-1-0288, OC230324)
  • Melanoma Research Foundation
  • Ovarian Cancer Research Alliance (MIG-2023-2-1018)
  • Chan Zuckerberg Initiative (2023-329680)
  • HERA Ovarian Cancer Foundation
  • Ludwig Institute for Cancer Research - Princeton Branch
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
ATR kinase, mTORC1, de novo cholesterol synthesis, lanosterol synthase, p16, DNA damage response, cholesterol metabolism, cancer cells, replication stress

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