Details

Autor(en) / Beteiligte

• Simoneschi, Daniele
• Rona, Gergely
• Zhou, Nan
• Jeong, Yeon-Tae
• Jiang, Shaowen
• Milletti, Giacomo
• Arbini, Arnaldo A.
• O’Sullivan, Alfie
• Wang, Andrew A.
• Nithikasem, Sorasicha
• Keegan, Sarah
• Siu, Yik
• Cianfanelli, Valentina
• Maiani, Emiliano
• Nazio, Francesca
• Cecconi, Francesco
• Boccalatte, Francesco
• Fenyö, David
• Jones, Drew R.
• Busino, Luca
• Pagano, Michele

Titel

CRL4AMBRA1 is a master regulator of D-type cyclins

Ist Teil von

• Nature (London), 2021-04, Vol.592 (7856), p.789-793

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2021

Link zum Volltext

Beschreibungen/Notizen

• D-type cyclins are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer1, but the mechanisms that regulate their turnover are still being debated2,3. Here, by combining biochemical and genetics studies in somatic cells, we identify CRL4AMBRA1 (also known as CRL4DCAF3) as the ubiquitin ligase that targets all three D-type cyclins for degradation. During development, loss of Ambrai induces the accumulation of D-type cyclins and retinoblastoma (RB) hyperphosphorylation and hyperproliferation, and results in defects ofthe 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 AMBRAI 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, CR1SPR-Cas9 screen identified AMBRAI as a regulator of the response to CDK4/6 inhibition. Loss of AMBRAI reduces sensitivity to CDK4/6 inhibitors by promoting the formation of complexes ofD-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 AMBRAI as a critical regulator ofthe RB pathway.