Open AccessCRL4AMBRA1 is a master regulator of D-type cyclins
Author(s) -
Daniele Simoneschi,
Gergely Róna,
Nan Zhou,
Yeong-Ho Jeong,
Suhua Jiang,
Giacomo Milletti,
Arnaldo Arbini,
Alfie O’sullivan,
Andrew A. Wang,
Sorasicha Nithikasem,
Sarah Keegan,
Yik Siu,
Valentina Cianfanelli,
Emiliano Maiani,
Francesca Nazio,
Francesco Cecconi,
Francesco Boccalatte,
David Fenyö,
Drew R. Jones,
Luca Busino,
Michele Pagano
Publication year - 2021
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-021-03445-y
Subject(s) - cyclin dependent kinase 6 , cyclin , retinoblastoma protein , biology , palbociclib , ubiquitin ligase , cancer research , cell cycle , regulator , microbiology and biotechnology , genetics , ubiquitin , cancer , gene , metastatic breast cancer , breast cancer
D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer 1 , but the mechanisms that regulate their turnover are still being debated 2,3 . Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4 AMBRA1 (also known as CRL4 DCAF3 ) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambra1 induces the accumulation of D-type cyclins and retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects of the nervous system that are reduced by treating pregnant mice with the FDA-approved CDK4 and CDK6 (CDK4/6) inhibitor abemaciclib. Moreover, AMBRA1 acts as a tumour suppressor in mouse models and low AMBRA1 mRNA levels are predictive of poor survival in cancer patients. Cancer hotspot mutations in D-type cyclins abrogate their binding to AMBRA1 and induce their stabilization. Finally, a whole-genome, CRISPR-Cas9 screen identified AMBRA1 as a regulator of the response to CDK4/6 inhibition. Loss of AMBRA1 reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes of D-type cyclins with CDK2. Collectively, our results reveal the molecular mechanism that controls the stability of D-type cyclins during cell-cycle progression, in development and in human cancer, and implicate AMBRA1 as a critical regulator of the RB pathway.