PXD058309-1

PXD058309 is an original dataset announced via ProteomeXchange.

Title	Development of compounds for targeted degradation of mammalian cryptochrome proteins
Description	The mammalian cryptochrome proteins (CRY1 and CRY2) are transcriptional repressors most notable for their role in circadian transcriptional feedback. Not all circadian rhythms depend on CRY proteins however, and the CRY proteins are promiscuous interactors that also regulate many other processes. In cells with chronic CRY deficiency, protein homeostasis is highly perturbed, with a basal increase in cellular stress and activation of key inflammatory signalling pathways. Here, we developed tools to delineate the specific effects of CRY reduction rather than chronic deficiency in order to better understand the direct functions of CRY proteins. Through a bioluminescence screen and immunoblot validation, we identified compounds that resulted in CRY reduction. Using these compounds, we found that circadian PERIOD2 (PER2) protein rhythms persisted under CRY-depleted conditions. By quantitative mass spectrometry, we found that CRY-depleted cells partially phenocopied the proteomic dysregulation of CRY-deficient cells, but showed minimal circadian phenotypes. We did however, also observe substantial off-target effects of these compounds on luciferase activity and could not ascertain a specific mechanism of action. This work therefore highlights both the utility and the challenges of targeted protein degradation and bioluminescence reporter approaches that are required to disentangle the contribution of CRY to circadian rhythmicity, homeostasis and innate immune regulation.
HostingRepository	PRIDE
AnnounceDate	2025-01-22
AnnouncementXML	Submission_2025-01-22_04:42:10.282.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sew Peak-Chew
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-26 21:53:25	ID requested
⏵ 1	2025-01-22 04:42:10	announced

10.1098/RSTB.2023.0342;

submitter keyword: cryptochrome,circadian rhythm, degradation

John S O'Neill
contact affiliation	MRC-LMB, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH
contact email	oneillj@mrc-lmb.cam.ac.uk
lab head
Sew Peak-Chew
contact affiliation	MRC-LMB
contact email	spc@mrc-lmb.cam.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD058309
     1. Label: PRIDE project
     2. Name: Development of compounds for targeted degradation of mammalian cryptochrome proteins