Department of Biochemistry and Molecular Pharmacology, Grossman School of Medicine, New York University, New York, NY, USA.
Uncovering the degrader of D-type cyclins – AMBRA1 is identified as the long-sought, major controller of D-type cyclins
D-type cyclins are fundamental to embryogenesis and score amongst the most frequently deregulated therapeutic targets in human cancer. Yet, decades after their discovery, the mechanisms regulating their turnover are still heavily debated. Using biochemical and somatic cell-genetics studies, we established CRL4AMBRA1 as the ubiquitin ligase of all three D-type cyclins, in both normal conditions and upon nutrient deprivation or genotoxic stress. We also found that, when we regulated the levels of D-type cyclins, AMBRA1 acts as a tumor suppressor in vivo, and its low mRNA levels are predictive of poor survival in cancer patients. Collectively, this work uncovers the molecular mechanism which controls D-type cyclins’ stability during cell-cycle progression, in development and in human cancer, and implicates AMBRA1 as a critical regulator of the retinoblastoma pathway.
Daniele was born in Rome, Italy, where he obtained a high school diploma for sciences from Liceo Scientifico Statale Farnesina and a degree in music from Conservatorio di Musica Santa Cecilia. In 2009, Daniele moved to the United States where he received a Chairman Award Scholarship from Manhattanville College, graduating valedictorian with a major in biochemistry and two minors: music and mathematics. Upon the completion of his undergraduate studies, Daniele joined the laboratory of Dr. Michele Pagano at the New York University Grossman School of Medicine, where he obtained his M.Phil. in Pathobiology and Translational Medicine, and a Ph.D. in Molecular Oncology and Tumour Immunology in 2021. As a graduate student, Daniele focused on the molecular and cellular mechanisms by which cullin-RING ubiquitin ligases (CRLs) regulate the execution of the cell-division cycle. Specifically, Daniele established that the tumor suppressor AMBRA1 acts as a CRL4 substrate receptor that dictates the specificity towards phosphorylated D-type cyclins during cell-cycle progression, and demonstrated that the deregulation of this pathway contributes to the pathogenesis of diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma in the United States and worldwide. To explore novel oncogenic pathways regulated by CRLs, Daniele then served as a Senior Research Coordinator in the laboratory of Dr. Michele Pagano, and was subsequently appointed to the position of faculty member in the Department of Biochemistry and Molecular Pharmacology at the New York University Grossman School of Medicine, where he currently serves as a Research Assistant Professor.