SNM1 (for sensitivity to nitrogen mustard) was originally identified in S. cerevisiae as a gene that conferred resistance to interstrand cross-linking agents, but not to other forms of DNA damage. In mammalian cells there are five identified members of the SNM1 gene family, and this application proposes to continue our studies on two of these genes termed SNM1 and SNM1B. Our preliminary findings show that both proteins interact with DNA-PK as has been shown by others with another member of the family termed Artemis. In addition, we have found that SNM1 is a component of a mitotic stress checkpoint that delays entry into metaphase. This novel checkpoint was recently defined by the characterization of the human Chfr gene, and is distinct from the well-characterized spindle checkpoint defined by the Mad and Bub proteins. Consistent with a role in a mitotic checkpoint, we have found that both SNM1 and SNM1B interact with the mitotic spindle protein Astrin in a two-hybrid screen, and that SNM1 co-immunoprecipitates with components of the anaphase-promoting complex. Finally, we have disrupted SNMI in the mouse and have observed both accelerated tumorigenesis and obesity phenotypes in the homozygous and heterozygous animals. The goals of this proposal are to examine the possible roles of SNM1 and SNM1B in NHEJ and DNA damage-induced cell cycle checkpoints, to further examine the function of these proteins in mitotic stress checkpoints, and to develop additional knockout models of these genes in mice as method to elucidate their function in tumor suppression.
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