PXD043637

PXD043637 is an original dataset announced via ProteomeXchange.

Title	FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress
Description	Oncogene-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.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_09:36:26.923.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Georgios Mermelekas
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-10 02:40:37	ID requested
⏵ 1	2025-05-06 09:36:27	announced

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;

submitter keyword: SCF ubiquitin ligase, Fanconi anaemia, FANCD2, replication stress,FBXL12

Janne Lehtiö
contact affiliation	Dept. Oncology Pathology, Karolinska Institutet, and Scilifelab, Stockholm, Sweden
contact email	janne.lehtio@ki.se
lab head
Georgios Mermelekas
contact affiliation	Karolinska Institutet
contact email	georgios.mermelekas@scilifelab.se
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043637
     1. Label: PRIDE project
     2. Name: FBXL12 degrades FANCD2 to regulate replication recovery and promote cancer cell survival under conditions of replication stress