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PXD043637

PXD043637 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleFBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress
DescriptionOncogene-induced replication stress constitutes an early obstacle for pre-cancerous cells to overcome to progress towards malignancy. Fanconi anaemia signalling represents a major genomic maintenance pathway that is activated in response to replication stress, impinging on stalled replication fork stability and recovery. We report that upon replication stress, phosphorylation of the FANCD2 N-terminus by CHK1 triggers FBXL12-dependent proteasomal degradation of FANCD2, facilitating clearance of FANCD2 at stalled replication forks and promoting replication recovery. Monoubiquitination of FANCD2 at K561 by the Fanconi anaemia core complex regulates clamping of the FANCD2-FANCI heterodimer onto DNA. To investigate if K561-monoubiquitination influences FANCD2 phosphorylation and/or polyubiquitination by FBXL12, we performed MS-based proteomics using HEK293 cells co-transfected with the monoubiquitin-deficient FANCD2 mutant (K561R) and FANCI, or a CHK1 phosphorylation-deficient FANCD2-AA (S8A/S10A) mutant as control. To induce rapid activation of CHK1, we inhibited WEE1 kinase using AZD1775, immunoprecipitated FANCD2 from chromatin extracts and performed MS analysis. The MS data revealed several phosphorylated N-terminal peptides in the K561R-FANCD2 sample, including S8, S10 and also S15 demonstrating that K561R is phosphorylated in response to replication stress induced by AZD1775.
HostingRepositoryPRIDE
AnnounceDate2025-05-06
AnnouncementXMLSubmission_2025-05-06_09:36:26.923.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterGeorgios Mermelekas
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-07-10 02:40:37ID requested
12025-05-06 09:36:27announced
Publication List
Brunner A, Li Q, Fisicaro S, Kourtesakis A, Viili, ä, inen J, Johansson HJ, Pandey V, Mayank AK, Lehti, ö J, Wohlschlegel JA, Spruck C, Rantala JK, Orre LM, Sangfelt O, FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress. Mol Cell, 83(20):3720-3739.e8(2023) [pubmed]
10.1016/j.molcel.2023.07.026;
Keyword List
submitter keyword: SCF ubiquitin ligase, Fanconi anaemia, FANCD2, replication stress,FBXL12
Contact List
Janne Lehtiö
contact affiliationDept. Oncology Pathology, Karolinska Institutet, and Scilifelab, Stockholm, Sweden
contact emailjanne.lehtio@ki.se
lab head
Georgios Mermelekas
contact affiliationKarolinska Institutet
contact emailgeorgios.mermelekas@scilifelab.se
dataset submitter
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