Regulation of cell proliferation by CRL ubiquitin ligases

New York University School Of Medicine, New York NY

Investigators

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Abstract

PROJECT ABSTRACT / SUMMARY Over four decades have elapsed since the discovery of the ubiquitin-proteasome system, yet our comprehension of its regulatory intricacies remains incomplete. This knowledge gap persists largely due to the limited characterization of the multitude of ubiquitin ligase enzymes, numbering approximately 600 in mammals. Within our laboratory, our primary focus has centered on unraveling the mechanisms through which Cullin-RING Ubiquitin Ligase (CRL) complexes orchestrate the three fundamental aspects of cellular life: growth, proliferation, and survival. Our contributions have been pivotal in elucidating the timing, spatial dynamics, and biological function of the CRL-mediated degradation of critical cellular regulators. Initially, our research endeavors were focused on delineating the temporal control of the mammalian cell cycle by the ubiquitin-proteasome system. Over time, our scope has broadened to encompass three distinct realms of investigation: cell signaling, cell cycle regulation, and the DNA damage response. This expansion has been facilitated by our discovery-oriented approach, which, in contrast to traditional hypothesis-driven methods, remains unbiased. Moreover, the results of these genetics and proteomics screens are not the end goal; they only set the stage for our mechanistic studies. This process often leads us to unexpected new territories, expanding our horizons to novel biological processes. Entering new research areas provides us with a broad vision that is less often attained within compartmentalized fields. Moreover, it enriches us by spurring new collaborations with other scientists and by prompting us to thoroughly learn new disciplines. The cross- pollination of diverse fields and ideas is one of the foundations of our modus operandi. In summary, we adopt a holistic and interdisciplinary approach to provide transformative insights into fundamental biological processes, particularly those governed by CRLs. The current proposed research endeavors will cover all the mechanistic studies conducted within our laboratory across the three aforementioned areas. Specifically, we intend to leverage our established expertise in the ubiquitin field to unearth the molecular mechanisms dictating CRL- mediated control over signal transduction pathways, cell cycle progression, and DNA repair. Furthermore, through a blend of biochemical and in vivo analyses, we aim to shed light on the regulatory mechanisms underlying general cellular homeostasis. Collectively, our expertise in the field of CRLs-mediated degradation, our validated methods for its investigation, our unique collection of reagents and tools, and the rigor of our prior research strongly ensure that our studies will continue to uncover novel CRL networks relevant to essential cellular processes, potentially unveiling novel insights into disease mechanisms.