Our laboratory is interested in understanding how the cell cycle is regulated in the context of organismal development. We are using the nematode Caenorhabditis elegans as a model system. The adult C. elegans has only 959 somatic cells, yet has multiple tissues, including muscle, skin, neurons, and intestine. Somatic cell divisions are developmentally programmed and largely invariant, thereby allowing detailed analysis of individual cell divisions through development.
We are currently focusing on understanding the functions of the cullin/RING finger class of ubiquitin-protein ligases, whose members target the ubiquitin-mediated degradation of a diverse set of substrates, including cell cycle regulators. Cullin/RING finger complexes comprise a core that includes cullins and RING finger proteins. The cullin gene family contains five major branches in metazoa. Our laboratory is currently exploring the in vivo functions of the C. elegans cullins CUL-1, CUL-2, and CUL-4. CUL-1 functions as a negative cell cycle regulator, which is required for cell cycle exit. In the absence of CUL-1, dividing cells are unable to respond to developmental cues to exit the cell cycle, and instead continue to proliferate thereby producing hyperplasia. CUL-2, in contrast, is a positive cell cycle regulator that is required for a number of different cell cycle events: G1 phase progression, chromatin condensation, and mitotic and meiotic progression. Finally, CUL-4 functions as a negative regulator of DNA replication that acts to restrict DNA replication licensing.
Our current projects involve both genetic and biochemical approaches to identify the substrates that must be ubiquitinated to allow the cullin-dependent cell cycle events to occur. We are also characterizing the proteins components in the cullin/RING finger complexes that are responsible for the observed cellular functions, as we expect multiple substrate-binding components will be present for each core complex. These studies on understanding basic aspects of cell cycle regulation will help to lay the foundation for the more long-range, comprehensive goal of understanding of how the cell cycle is regulated through development.
Cellular biology; molecular genetics; regulation of cell division in Caenorhabditis elegans
Kipreos, E. T. and van den Heuvel, S. 2019. Developmental control of the cell cycle: insights from C. elegans. Genetics 211: 797-829.
Chaudhari, S. N. and Kipreos, E. T. 2018. The energy maintenance theory of aging: maintaining energy metabolism to allow longevity. BioEssays 40: e1800005.
Mukherjee, M., Chaudhari, S. N., Balachandran, R. S., Vagasi, and Kipreos, E. T. 2017. Dafachronic acid inhibits C. elegans germ cell proliferation in a DAF-12-dependent manner. Developmental Biology 432: 215-221.
Chaudhari, S. N. and Kipreos, E. T. 2017. Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways. Nature Communications 8: 182.
Vagasi, A. S., Rahman, M. M., Chaudhari, S. N., and Kipreos, E. T. 2017. Primary culture system for germ cells from Caenorhabditis elegans tumorous germline mutants. Bio-protocol 7: BioProtoc.2424.
Chaudhari, S.N., Mukherjee, M., Vagasi, A.S., Bi, G., Rahman, M.M., Nguyen, C.Q., Paul, L., Selhub, J., and Kipreos, E.T. 2016. Bacterial folates provide an exogenous signal for C. elegans germline stem cell proliferation. Developmental Cell 38: 33-46.
Balachandran, R.S., Heighington, C.S., Starostina, N.G., Anderson, J.W., Owen, D.L., Vasudevan, S., and Kipreos, E.T. 2016. The ubiquitin ligase CRL2(ZYG11) targets cyclin B1 for degradation in a conserved pathway that facilitates mitotic slippage. The Journal of Cell Biology 215: 151-166.
Starostina, N.G., Simpliciano, J.M., McGuirk, M.A., and Kipreos, E.T. 2010. CRL2LRR-1 targets a CDK inhibitor for cell cycle control in C. elegans and actin-based motility regulation in human cells. Developmental Cell, 19: 753-756.
Akella, J.S., Wloga, D., Kim, J. Starostina, N.G., Lyons-Abbott, S., Morrissette, N.S., Dougan, S.T., Kipreos, E.T., and Gaertig, J. 2010. MEC-17 is an alpha-tubulin acetyltransferase. Nature, 467: 218-22.
Kim, Y., Starostina, N.G., and Kipreos, E.T. 2008. The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing. Genes & Development 22: 2507-2519. Starostina, N.G., Lim, J., Schvarzstein, M., Wells, L., Spence, A.M., and Kipreos, E.T. 2007. A CUL-2 ubiquitin ligase containing three FEM proteins degrades TRA-1 to regulate C. elegans sex determination. Developmental Cell 13: 127-139.
Kipreos, E.T. 2005. C. elegans cell cycles: invariance and stem cell divisions. Nature Reviews Molecular Cell Biology 6: 766-776.
Zhong, W., H. Feng, F.E. Santiago, and Kipreos, E.T. 2003. CUL-4 ubiquitin ligase maintains genome stability by restraining DNA replication licensing. Nature 423: 885-889.
Feng, H., W. Zhong, G. Punkosdy, S. Gu, L. Zhou, E.K. Seabolt, and Kipreos, E.T. 1999. CUL-2 is required for the G1-to-S phase transition and mitotic chromosome condensation in Caenorhabditis elegans. Nature Cell Biology 1: 486-492.