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PreprintCited 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.·2023·EMBO Reports
DOI 10.1101/2023.10.27.564195PMC PMC12287318

Preprint — published as 10.1038/s44319-025-00451-3 · Paper page

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Abstract

DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback mechanisms. Key mediators of the DNA damage response and cellular metabolic regulation include Ataxia Telangiectasia and Rad3-related protein (ATR) and the mechanistic Target of Rapamycin Complex 1 (mTORC1), respectively. Previous studies have established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms by which mTORC1 is activated in this context remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. Here, we demonstrate that ATR promotes mTORC1 activity across various cellular models under basal conditions. This effect is particularly enhanced in cells following the loss of p16, which we have previously associated with hyperactivation of mTORC1 signaling and here found have increased ATR activity. Mechanistically, we found that ATR promotes de novo cholesterol synthesis and mTORC1 activation through the upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Furthermore, the attenuation of mTORC1 activity resulting from ATR inhibition was rescued by supplementation with lanosterol or cholesterol in multiple cellular contexts. This restoration corresponded with enhanced localization of mTOR to the lysosome. 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
openRxiv
Published
2023-10-28
Volume
26
Issue
14
Pages
3574-3593
ISSN
1469-221X (ISSN-L)
DOI
10.1101/2023.10.27.564195
PMC
PMC12287318
OpenAlex
W4411281801
Cited by
5
References
1
Citations by year
2026: 1 · 2025: 3 · 2024: 1
FWCI
1.19
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
  • Melanoma Research Foundation
  • Melanoma Research Alliance
  • Ovarian Cancer Research Alliance (MIG-2023-2-1018)
  • Chan Zuckerberg Initiative (2023-329680)
  • National Institutes of Health (1s10od023402-01a1, 1s10od032141-01)
  • NIH Office of the Director (S10OD032141, S10OD023402)
  • National Cancer Institute (R37CA240625, R01CA301573, P50CA272218, P30CA047904, R01CA259111)
  • National Institute of General Medical Sciences (R35GM155379, T32GM133332)
  • Congressionally Directed Medical Research Programs (HT9425-23-1-0288, OC230324)
  • DOD Peer Reviewed Cancer Research Program (HT9425-23-1-0288, OC230324)
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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