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Updated: Jun 16, 2025

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ATR promotes mTORC1 activity via de novo cholesterol synthesis

Naveen Kumar Tangudu1,2, Alexandra N Grumet3, Richard Fang1,2

  • 1Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

EMBO Reports
|June 13, 2025
PubMed

Insights

The ATR kinase promotes mTORC1 activity by regulating cholesterol synthesis, linking DNA damage response and cellular metabolism. This pathway is active in both normal and cancer cells, particularly when p16 is reduced.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • DNA damage and cellular metabolism are interconnected through feedback loops.
  • ATR and mTORC1 are key mediators of these pathways.
  • ATR regulates mTORC1 during replication stress, but mechanisms and basal activity are unclear.

Purpose of the Study:

  • To investigate the role of ATR in regulating mTORC1 activity under basal conditions.
  • To elucidate the molecular mechanisms linking ATR and mTORC1.
  • To explore the impact of p16 on the ATR-mTORC1 axis.

Main Methods:

  • Cell culture (human cancer and normal cells, mouse normal cells)
  • siRNA-mediated knockdown (p16)
  • Western blotting
  • Cholesterol synthesis assays
  • Immunofluorescence microscopy

Main Results:

  • ATR promotes mTORC1 activity in various cell types under basal conditions.
  • p16 knockdown enhances ATR and mTORC1 activity in cancer cells.
  • ATR upregulates lanosterol synthase (LSS), boosting cholesterol synthesis and mTORC1 activation.
  • This ATR-dependent pathway is independent of CHK1 and TSC, and distinct from ATM signaling.
  • ATR-mediated cholesterol increase correlates with enhanced lysosomal localization of mTOR.

Conclusions:

  • ATR signaling modulates cholesterol metabolism to regulate mTORC1 activity.
  • This novel ATR-cholesterol-mTORC1 axis provides a link between DNA damage response and cellular metabolism.
  • The pathway may be particularly relevant in cancer cells.
Keywords:
CholesterolLanosterol SynthaseLysosomeMetabolismp16

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