Robert Weiss
Professor of Molecular Genetics
Robert Weiss

Phone

607-253-4443

Address

Department of Biomedical Sciences
T2006C, Vet Research Tower
Cornell University
Ithaca, NY 14853-2703

Email

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Department Profile

Research Description

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.

Publications

  • Zhu, M. and R. S. Weiss. 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. [ PDF ]
  • Levitt, P. S., M. Zhu, A. Cassano, S. A. Yazinski, H. Liu, J. Darfler, R. M. Peters, and R. S. Weiss. 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. [ PDF ]
  • Francia, S., R. S. Weiss, and F. d'Adda di Fagagna. 2007. Need telomere maintenance? Call 911. Cell Division 2:3. [ PDF ]
  • Francia, S., R. S. Weiss, M. P. Hande, R. Freire, and F. d'Adda di Fagagna. 2006. Telomere and telomerase modulation by the mammalian Rad9/Rad1/Hus1 DNA-damage-checkpoint complex. Curr. Biol. 16: 1551-1558. [ PDF ]
  • Levitt, P. S., H. Liu, C. Manning, and R. S. Weiss. 2005. Conditional inactivation of the mouse Hus1 cell cycle checkpoint gene. Genomics 86:212-224.
    [ PDF ]
  • Weiss, R. S., P. Leder, and C. Vaziri. 2003. Critical role for mouse Hus1 in a S-phase DNA damage cell cycle checkpoint. Mol. Cell. Biol. 23:791-803. [ PDF ]
  • Weiss, R. S., S. Matsuoka, S. J. Elledge, and P. Leder. 2002. Hus1 acts upstream of Chk1 in a mammalian DNA damage response pathway. Curr. Biol. 12:73-77. [ PDF ]
  • Weiss, R. S., T. Enoch, and P. Leder. 2000. Inactivation of mouse Hus1 results in genomic instability and impaired responses to genotoxic stress. Genes & Dev. 14: 1886-1898. [ PDF ]