Phone: 607 253 4443
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in Hus1-null cells
Metaphase spreads were prepared from primary cultures of 9.5 dpc Hus1 embryos and stained with Giemsa.
(A) A normal metaphase from a Hus1+/+ embryo
(B,C) Metaphases from Hus1-/- embryos displaying chromatid breaks and other abnormalities.
Size bar = 12.5 µm
(click for larger image)
Research positions are available for:
The successful duplication of a human cell requires error-free replication of the 3 X 109 bp genome and its equal segregation to daughter cells. This demanding task must be performed accurately millions of times over the lifetime of an individual, and its fidelity can be impaired by a variety of common genotoxic stresses, such as DNA-damaging UV light. Fortunately, cells have a variety of safeguards and repair pathways that act to preserve genomic integrity. The significance of these mechanisms is highlighted by the fact that defects in them can have severe consequences, including tumor development and infertility. My laboratory investigates the functions of mammalian genome maintenance pathways at the molecular, cellular, and organismal levels.
We focus in part on analysis of the mouse cell cycle checkpoint gene Hus1 as a tool to decipher how the mammalian DNA damage checkpoint apparatus operates and to evaluate the physiological consequences of genomic instability in an animal model. We previously inactivated Hus1 in the mouse by gene targeting, and found that Hus1 loss causes chromosomal instability, impaired cellular responses to genotoxic stress, and embryonic lethality. To determine the roles of Hus1 in post-natal development and tumorigenesis, we have developed conditional knockout mice in which Hus1 can be deleted in specific adult tissues, such as the mammary gland, hematopoietic system, or skin. We also have used a novel hypomorphic Hus1 allele to generate a series of cells and mice featuring incremental reductions in Hus1 expression. This permits analysis of the impact of reduced Hus1 function while bypassing the severe phenotypes associated with complete Hus1 loss. These novel genetic approaches hold promise for revealing the physiological functions of an essential checkpoint pathway.
A second line of investigation centers on how genomic stability and DNA damage responses are impacted by cellular nucleotide levels. For this purpose, we generated transgenic mice that broadly over-express components of the enzyme ribonucleotide reductase, which catalyzes the rate limiting step in nucleotide biosynthesis. Interestingly, these animals demonstrate a dramatic lung tumor predisposition, developing papillary lung adenocarcinomas that resemble common human lung cancers. Current experiments are aimed at elucidating the molecular mechanism of ribonucleotide reductase-induced tumorigenesis, including the basis for the intriguing tissue specificity. In sum, the studies described here should provide important new insights into how genomic instability stemming from altered nucleotide metabolism or checkpoint dysfunction impacts organismal development, cellular responses to genotoxic compounds, and tumorigenesis.
For information on related research at Cornell University, please visit the R3 Group Homepage.
- Lyndaker, A.M., Lim, P.X., Mleczko, J.M., Diggins, C., Holloway, J.K., Holmes, R.J., Kan, R., Schlafer, D.H., Freire, R., Cohen, P.E., and Weiss, R.S. (2013) Conditional inactivation of the DNA damage response gene Hus1 in mouse testis reveals separable roles for components of the RAD9-RAD1-HUS1 complex in meiotic chromosome maintenance. PLoS Genetics 9(2): e1003320. doi:10.1371/journal.pgen.1003320. PubMed
- Balmus, G., Zhu, M., Mukherjee, S., Lyndaker, A.M., Hume, K.R., Lee, J., Riccio, M.L., Reeves, A.P., Sutter, N.B., Noden, D.M., Peters, R.M., and Weiss, R.S. (2012) Disease severity in a mouse model of Ataxia Telangiectasia is modulated by the DNA damage checkpoint gene Hus1. Human Molecular Genetics 21:3408–3420. PubMed
- Daugherity, E.K., Balmus, G., Al Saei, A., Moore, E.S., Abi Abdallah, D., Rogers, A.B., Weiss, R.S., and Maurer, K.J. (2012) The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease. Cell Cycle 11:1918-1928. PubMed
- Ylikallio, E., Page, J.L., Xu, X., Lampinen, M., Bepler, G., Ide, T., Tyynismaa, H., Weiss, R.S. and Suomalainen, A. (2010). Ribonucleotide Reductase is not limiting for mitochondrial DNA copy number in mice. Nucleic Acids Res. 38: 8208-8218. PubMed
- Yazinski, S.A., Westcott, P.M., Ong, K., Pinkas, J., Peters, R.M., and Weiss, R.S. (2009) Dual inactivation of Hus1 and p53 in the mouse mammary gland results in accumulation of damaged cells and impaired tissue regeneration. Proceedings of the National Academy of Science USA 106: 21282–21287. PubMed
- Xu, X., Page, J.L., Surtees, J.A., Liu, H., Lagedrost, S., Lu, Y., Bronson, R., Alani, E., Nikitin, A. Yu., and Weiss, R.S. (2008) Broad overexpression of ribonucleotide reductase genes in mice specifically induces lung neoplasms. Cancer Res. 68: 2652-2660. PubMed
- Levitt, P.S., Zhu, M., Cassano, A., Yazinski, S.A., Liu, H., Darfler, J., Peters, R.M., and Weiss, R.S. (2007) Genome maintenance defects in cultured cells and mice following partial inactivation of the essential cell cycle checkpoint gene Hus1. Mol. Cell. Biol. 27: 2189-2201. PubMed
- Zhu, M. and Weiss, R.S. (2007) Increased common fragile site expression, cell proliferation defects, and apoptosis following conditional inactivation of mouse Hus1 in primary cultured cells. Mol. Biol. Cell 18: 1044-1055. PubMed
- Francia, S., Weiss, R.S., Hande, M.P., Freire, R., and d'Adda di Fagagna, F. (2006) Telomere and telomerase modulation by the mammalian Rad9/Rad1/Hus1 DNA-damage-checkpoint complex. Curr. Biol. 16: 1551-1558. PubMed
- Levitt, P.S., Liu ,H., Manning, C., and Weiss, R.S. (2005) Conditional inactivation of the mouse Hus1 cell cycle checkpoint gene. Genomics 86:212-224. PubMed