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AMBRA1 interacts with the E3 ubiquitin ligase CRL4DDB1 complex to regulate the stability of D-type cyclins, key regulators of the G1\u2013S phase transition. However, whether AMBRA1 has a role in the S phase remains to be elucidated. Here, we show that AMBRA1 affects the turnover of p21Waf1\/Cip1 and p27Kip1 by coupling the CRL4DDB1 complex to these proteins. In the absence of AMBRA1, the increased stability of p21Waf1\/Cip1, rather than p27Kip1, resulted in the accumulation of replication stress. Mechanistically, the excess of p21Waf1\/Cip1 during the S phase resulted in more PCNA-bound p21Waf1\/Cip1, negatively affecting the binding of FEN1 to PCNA, which left under-replicated DNA. Consequently, AMBRA1-depleted cells are sensitive to FEN1 inhibition. Aberrantly low levels of AMBRA1 occurring in Sonic Hedgehog-type medulloblastomas correlate with high levels of p21Waf1\/Cip1 and a worse prognosis. Finally, AMBRA1 and p21 levels may serve as biomarkers for patient stratification and treatment in medulloblastoma.<\/jats:p>","DOI":"10.1093\/nar\/gkag595","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T11:40:51Z","timestamp":1782214851000},"source":"Crossref","is-referenced-by-count":0,"title":["Ubiquitin-dependent degradation of p27Kip1 and p21Waf1\/Cip1 by AMBRA1 ensures G1 and S phase progression and limits replication stress"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2391-342X","authenticated-orcid":false,"given":"Giacomo","family":"Milletti","sequence":"first","affiliation":[{"name":"DNA Replication and Cancer Group, Danish Cancer Institute , 2100Copenhagen ,","place":["Denmark"]},{"name":"Dipartimento di Scienze biotecnologiche di base, cliniche intensivologiche e perioperatorie, Universit\u00e0 Cattolica del Sacro Cuore , 00168Rome 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