During the eukaryotic cell cycle, highly regulated events culminate in exact duplication of one cell into two. Elaborate regulatory mechanisms provide for the faithful execution of all events ensuring, for example, that DNA replication is always completed before mitosis. Regulatory mechanisms of cell division processes preserve the genetic integrity of the cell and, consequently, the organism. Defects in cell division underlay some human diseases, including cancer.
We study regulatory controls called checkpoints that ensure that DNA replication and DNA repair are completed before mitosis. Put simply, normal cells with DNA damage do not replicate their DNA nor do they undergo mitosis. Rather, these damaged cells wait, arresting at checkpoints, until repair is complete, for mitosis with a damaged chromosome is highly deleterious to the cell. We study the genetic and molecular details underlying checkpoint controls in yeast, a typical eukaryotic cell amenable to the extensive genetic analysis required to understand complex biological systems. We have now identified genes and proteins involved in recognizing DNA damage and in subsequent signaling events, and now seek to understand the molecular details of how these regulatory proteins act at the molecular level.
We also investigate the importance of checkpoint controls to the cells genetic integrity by studying the fate of cells that divide with a broken chromosome. Such cells undergo a myriad of chromosomal events, termed genomic instability, the basis for which we are only now beginning to unravel.
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Admire, A., L. Shanks, N. Danzl, M. Wang, U. Weier, W. Stevens, E. Hunt, and T. Weinert. 2006. Cycles of chromosome instability are associated with a fragile site and are increased by defects in DNA replication and checkpoint controls in yeast. Genes and Development 20: 159-173.
Weinert, T. 2005. Do telomeres ask checkpoint proteins: "gimme shelter-in"? Developmental Cell 9: 725-726.
Michelson, R.J., S. Rosenstein, and T. Weinert. 2005. A telomeric repeat sequence adjacent to a DNA double-stranded break produces an anticheckpoint. Genes and Development 19: 2546-2559.
Weinert, T., E. Little, L. Shanks, A. Admire, R. Gardner, C. Putnam, R. Michelson, K. Nyberg, and P. Sundareshan. 2000. Details and concerns regarding the G2/M DNA damage checkpoint in budding yeast. Cold Spring Harbor Symposia on Quantitative Biology 65: 433-441.
Nyberg, K.A., R.J. Michelson, C.W. Putnam, and T.A. Weinert. 2002. Toward maintaining the genome: DNA damage and replication checkpoints. Annual Review of Genetics 36: 617-656.
Michelson, R.J., and T. Weinert. 2000. Closing the gaps among a web of DNA repair disorders. Bioessays 22: 966-969.
