Lead Inventor: Howard Lieberman, Ph.D.
See also: case number IR#585
Screening tools for response to DNA damage and prevention of DNA damage:
Rad9 was previously identified by Dr. Lieberman (US Patent 5,882,862) and promotes cell survival through the regulation of DNA repair and the activation of cell cycle checkpoints induced by DNA damage. Mouse embryonic stem (ES) cells with a targeted deletion of Mrad9, the mouse ortholog of the gene, were created to evaluate the function of the protein in mammals. Mrad9-/- ES cells and Mrad9+/- mice are both available for use in cancer research. Both the mouse and cell lines, with deficient responses to DNA-damaging insults caused by radiation and chemicals, provide a way to screen for novel cancer therapeutics.
Mrad9-/- ES cells are viable and demonstrate a high frequency of spontaneous chromosome aberrations and hprt mutations, indicating the role of Rad9 in regulating genomic integrity These cells also have increased sensitivity versus wild type cells to UV light, gamma rays, hydroxyurea, and numerous alkylating agents.
Mrad9-/- mice are embryonic lethal; however the heterozygote line provides a tool to investigate the effects of haploinsufficiency of proteins involved in DNA repair pathways. Combined haploinsufficiency for ATM, a protein important in DNA double-strand break repair, and Rad9 demonstrates the utility of this approach with an increased sensitivity to transformation by radiation than found in cells haploinsufficient for only one protein. Mice haploinsufficient for one or both of these proteins are also more prone to cataractogenesis.
Additionally mice generated with Mrad9 deleted only in keratinocytes provided the opportunity to examine further the function of the gene in tumor development. The targeted deletion of Rad9 in mouse skin keratinocytes enhances genotoxin-induced tumor development.
The animals and tissues described here therefore provide valuable screening tools for understanding the genetic basis of the cellular and organismal response to DNA damage, and for identifying treatments/protection agents to prevent DNA damage and the potential deleterious effects such as tumorigenesis and disease that can ensue.
DNA Damage Prevention - Commercial Applications:
Provides models for:
- Screen or assay of agents that protect from induction of DNA damage; analysis of genetic susceptibility to carcinogenesis and DNA damaging agents
- Studying cell survival in response to damage when other regulatory genes are blocked in ES Mrad9+/- and Mrad9-/- cells e.g. via RNAi
- Mrad9+/- mice provide opportunity to assess in vivo the effect of haploinsufficiency and to study (via genetic crosses) its interactions with other genes that control cellular responses to DNA damage
- Mrad9+/-, ATM+/- double heterozygous mice provide radiation sensitivity animal models for the development of occupational and therapeutic radiation exposure effects
Advantages:
- Provides unique cell lines and mouse models with multiple uses
- Mrad9 is a unique gene with multiple cell functions
- Viable ES cell lines and heterozygous mice provide a novel screening tool for DNA damaging agents and for agents that can protect against the damage induced
Patent Status: US Patent 5,882,862 issued 3/16/99
Related Publications:
Molecular and Cell Biology (2004) 24: 7235-48;Cancer Research (2005) 65: 933-38;Cancer Research (2008) 68: 5552-6;Radiation Research (2007) 168: 567-73
