Ubiquitin-dependent degradation of p21Waf1/Cip1 is mediated by AMBRA1 to limit DNA replication stress
Milletti, G.; Cadeddu, G.; Adelantado Rubio, A.; Ferraina, C.; Keuper, K.; Munk, S.; De Stefanis, C.; Quacquarini, D.; Rossi, S.; Mastronuzzi, A.; Locatelli, F.; Grumati, P.; Cianfanelli, V.; Nazio, F.; Bartek, J.; Maya-Mendoza, A.; Cecconi, F.
Show abstract
The cell cycle is a fundamental process that orchestrates the events that lead to cell replication and division. AMBRA1 is a scaffold factor that interacts with the E3 ubiquitin ligase CRL4-DDB1 complex to regulate the stability of cyclin D-type proteins, key regulators of the G1/S phase transition. However, how cells complete S-phase and coordinate the speed of DNA synthesis is still to be fully elucidated. Here we demonstrate that AMBRA1 affects the turnover of p21Waf1/Cip1 and p27Kip1, by coupling the CRL4-DDB1 complex directly to these proteins. 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 AMBRA1-depleted cells with consequent high p21Waf1/Cip1 are sensitive to the inhibition of lagging-strand DNA synthesis. Of clinical relevance, low levels of AMBRA1 in Sonic-Hedgehog medulloblastoma correlate with a worse prognosis, suggesting that AMBRA1 expression levels could be an informative criterion for patient stratification and treatment.
Matching journals
The top 2 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- ANP32E drives vulnerability to ATR inhibitors by inducing R-loops-dependent Transcription Replication Conflicts in Triple Negative Breast Cancer 99%
- SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade 99%
- CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts 99%
Similar papers in this journal
- Whole genome doubling confers unique genetic vulnerabilities on tumor cells 99%
- Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint 98%
- Asymmetric Engagement of Dimeric CRL3KBTBD4 by the Molecular Glue UM171 Licenses Degradation of HDAC1/2 Complexes 98%
Similar papers in this journal
Similar papers in this journal
- linc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells 98%
- Transcriptional Control Of Calmodulin By CAMTA Regulates Neural Excitability 97%
- Interaction mapping of endoplasmic reticulum ubiquitin ligases identifies modulators of innate immune signalling 97%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.