PXD061265

PXD061265 is an original dataset announced via ProteomeXchange.

Title	ATR promotes mTORC1 activity via de novo cholesterol synthesis
Description	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 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 con-texts. This restoration corresponded with enhanced localization of mTOR to the lysosome. Collectively, our findings link ATR and mTORC1 signaling through the modulation of cholesterol metabolism.
HostingRepository	PRIDE
AnnounceDate	2025-04-01
AnnouncementXML	Submission_2025-04-01_06:11:04.948.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Cassandra Happe
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-27 04:49:12	ID requested
⏵ 1	2025-04-01 06:11:05	announced

Dataset with its publication pending

submitter keyword: human

SKMEL28

p16 knockdown

Katherine Aird
contact affiliation	Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine,UPMC Hillman Cancer Center, Pittsburgh, PA
contact email	katherine.aird@pitt.edu
lab head
Cassandra Happe
contact affiliation	University of Pittsburgh
contact email	chappe@pitt.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD061265
     1. Label: PRIDE project
     2. Name: ATR promotes mTORC1 activity via de novo cholesterol synthesis