PXD053083-1

PXD053083 is an original dataset announced via ProteomeXchange.

Title	Ubiquitin-dependent degradation of p21Waf1/Cip1 is mediated by AMBRA1 to limit DNA replication stress
Description	The cell cycle orchestrates the events that lead to cell replication and division. AMBRA1 is a scaffold factor that interacts with the E3 ubiquitin ligase DDB1-CRL4 complex to regulate the stability of Cyclin D-type proteins, key regulators of the G1-S phase transition. However, the role of AMBRA1 in regulating the stability of other cell-cycle-related proteins is far from being fully characterized. Here we demonstrate that AMBRA1 affects the turnover of p21Waf1/Cip1 and p27Kip1, by coupling the DDB1-CRL4 complex directly to these proteins mainly independent of Cyclin D. In the absence of AMBRA1, the increased stability of p21Waf1/Cip1, rather than p27Kip1, resulted in the accumulation of replication stress by leaving under-replicated DNA during the S phase. We also found that cells with a low expression of AMBRA1 and high p21Waf1/Cip1 are sensitive to drugs that interfere with the lagging-strand DNA synthesis. Of clinical relevance, low levels of AMBRA1 and high levels of p21Waf1/Cip1 Sonic-Hedgehog medulloblastoma correlate with a worse prognosis, suggesting that tumors with low levels of AMBRA1 can be a criterion for patient stratification and treatment.
HostingRepository	PRIDE
AnnounceDate	2026-06-29
AnnouncementXML	Submission_2026-06-28_16:58:30.179.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Giacomo Milletti
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-13 10:31:58	ID requested
⏵ 1	2026-06-28 16:58:31	announced

10.1093/nar/gkag595;

Milletti G, Cadeddu G, Adelantado-Rubio A, Ferraina C, Keuper K, Munk SHN, De Stefanis C, Quacquarini D, Rossi S, Mastronuzzi A, Locatelli F, Grumati P, Cianfanelli V, Nazio F, Bartek J, Maya-Mendoza A, Cecconi F, Ubiquitin-dependent degradation of p27Kip1 and p21Waf1/Cip1 by AMBRA1 ensures G1 and S phase progression and limits replication stress. Nucleic Acids Res, 54(12):(2026) [pubmed]

submitter keyword: AMBRA, DNA, p21

Milletti Giacomo
contact affiliation	Danish Cancer Institute
contact email	gimi@cancer.dk
lab head
Giacomo Milletti
contact affiliation	Danish Cancer Institute
contact email	gimi@cancer.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD053083
     1. Label: PRIDE project
     2. Name: Ubiquitin-dependent degradation of p21Waf1/Cip1 is mediated by AMBRA1 to limit DNA replication stress