# Regulation of the cell proliferation by CRL ubiquitin ligases

> **NIH NIH R35** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $339,000

## Abstract

PROJECT ABSTRACT / SUMMARY
More than 30 years have passed since the discovery of the ubiquitin-proteasome system, yet
we still lack comprehensive insights into its regulatory mechanisms. This limitation arises
because most of the approximately 600 ubiquitin ligase enzymes in mammals remain largely
uncharacterized. Our laboratory has focused on how Cullin-RING Ubiquitin Ligase (CRL)
complexes control the three essential dimensions of cellular life: proliferation, survival, and
differentiation. We have played a central role in elucidating how, when, where and, most
importantly, why CRLs mediate the degradation of key cellular regulators. The research in my
laboratory initially focused on the paradigm of the timed regulation of the mammalian cell cycle
by the ubiquitin-proteasome system, which we established a number of years ago. We have
since expanded our research into five fields of study: (i) cell signaling, (ii) cell cycle control, (iii)
the DNA damage response, (iv) oncology, and (v) the circadian clock. This expansion of our
interests has been possible thanks to our discovery-driven approach that, in contrast to the
more common hypothesis-driven approach, is unbiased. Yet, the results of genetics and
proteomics screens are not our end goal, but they guide us to explain the underlying biological
concepts and mechanisms. Importantly, they often lead us to unexpected and unexplored new
territories, opening our horizons. In summary, we use a comprehensive and interdisciplinary
approach to break new grounds and make transformative discoveries that will provide new
mechanistic insights into fundamental biological processes, particularly those processes that are
regulated by CRLs. The current proposed research will cover all the mechanistic studies
performed in our laboratory concerning areas i-iii listed above. In particular, we will leverage our
recognized expertise in the ubiquitin field to discover molecular mechanisms by which CRLs
control signal transduction pathways, autophagy, cell cycle progression, and DNA repair.
Moreover, we will perform biochemical, cellular and in vivo analyses to illuminate how CRLs are
regulated to function as switches between diverse cell fates. These findings will substantially
advance our understanding of the proper execution of crucial cellular processes, potentially
shedding light on the etiologies and treatments of human diseases.

## Key facts

- **NIH application ID:** 10149352
- **Project number:** 5R35GM136250-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** MICHELE PAGANO
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $339,000
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149352

## Citation

> US National Institutes of Health, RePORTER application 10149352, Regulation of the cell proliferation by CRL ubiquitin ligases (5R35GM136250-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10149352. Licensed CC0.

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