The long-term goal of this research is to understand cell cycle regulation in the context of animal development. Regulated proteolysis is central to the control of the cell cycle, and defects in ubquitin- mediated proteolysis have been linked to cancer. Cell cycle-dependent protein degradation occurs principally through the ubiquitin proteolytic pathway. The human CUL2 ubiquitin ligase functions as part of a tumor suppressor complex to prevent cancer, but its role in regulating the cell cycle has not been directly studied. In C. elegans, CUL-2 is required for multiple aspects of cell cycle regulation, including: the G1 to S phase transition;chromosome condensation;the meiosis II metaphase to anaphase transition;mitotic progression;and the degradation of mitotic cyclin B. CUL-2 has additional roles in the regulation of polarity and sex determination. CUL-2 functions as a central component of a multisubunit ubiquitin ligase that employs distinct substrate recognition subunits (SRSs). The identity of the SRSs that recognize substrates in several of the CUL-2-dependent cell cycle pathways are unknown, as are the critical substrates, whose ubiquitination allows the cell cycle events to occur. The experiments in this proposal will clarify the functions of the CUL-2 ubiquitin ligase in three major ways. First, SRSs and proteins that physically associate with the CUL-2 complex will be identified by immunoaffinity purification and two-hybrid screens. Interacting proteins will be characterized for cellular function and expression pattern. Second, the substrates that are ubiquitinated by CUL-2 complexes to regulate the cell cycle will be identified by a modified affinity purification protocol and two-hybrid screen. These substrates will be characterized to determine the CUL-2-dependent process in which they function and their role in that process. Finally, genetic screens for suppressors of CUL-2 complex SRS genes will identify interacting genes that either modulate CUL-2 complex activity, allow a bypass of CUL-2 function, or are critical substrates of CUL-2. Understanding the molecular pathways through which CUL-2 regulates the cell cycle will provide important insights into the control of fundamental cell cycle events. Cancer derives from unregulated cell proliferation, and a complete understanding of cell cycle control will provide a foundation for understanding cancer biology and developing anti-cancer therapeutics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Hamlet, Michelle R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Georgia
Schools of Arts and Sciences
United States
Zip Code
Chaudhari, Snehal N; Kipreos, Edward T (2018) The Energy Maintenance Theory of Aging: Maintaining Energy Metabolism to Allow Longevity. Bioessays 40:e1800005
Vagasi, Alexandra S; Rahman, Mohammad M; Chaudhari, Snehal N et al. (2017) Primary Culture System for Germ Cells from Caenorhabditis elegans Tumorous Germline Mutants. Bio Protoc 7:
Chaudhari, Snehal N; Kipreos, Edward T (2017) Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways. Nat Commun 8:182
Balachandran, Riju S; Kipreos, Edward T (2017) Addressing a weakness of anticancer therapy with mitosis inhibitors: Mitotic slippage. Mol Cell Oncol 4:e1277293
Mukherjee, Madhumati; Chaudhari, Snehal N; Balachandran, Riju S et al. (2017) Dafachronic acid inhibits C. elegans germ cell proliferation in a DAF-12-dependent manner. Dev Biol 432:215-221
Dankert, John F; Pagan, Julia K; Starostina, Natalia G et al. (2017) FEM1 proteins are ancient regulators of SLBP degradation. Cell Cycle 16:556-564
Balachandran, Riju S; Heighington, Cassandra S; Starostina, Natalia G et al. (2016) The ubiquitin ligase CRL2ZYG11 targets cyclin B1 for degradation in a conserved pathway that facilitates mitotic slippage. J Cell Biol 215:151-166
Chaudhari, Snehal N; Mukherjee, Madhumati; Vagasi, Alexandra S et al. (2016) Bacterial Folates Provide an Exogenous Signal for C. elegans Germline Stem Cell Proliferation. Dev Cell 38:33-46
Starostina, Natalia G; Kipreos, Edward T (2012) Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors. Trends Cell Biol 22:33-41
Sawyer, Jacob M; Glass, Stephanie; Li, Trudy et al. (2011) Overcoming redundancy: an RNAi enhancer screen for morphogenesis genes in Caenorhabditis elegans. Genetics 188:549-64

Showing the most recent 10 out of 17 publications