Ubiquitin-dependent degradation of p21Waf1/Cip1 is mediated by AMBRA1 to limit DNA replication stress

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Giacomo Milletti  

LAB HEAD: Milletti Giacomo

PROVIDER: PXD053083 | Pride | 2026-06-29

REPOSITORIES: Pride