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The Kaufmann laboratory is concerned with the mechanisms of human carcinogenesis with special interest in cell cycle checkpoints that act to preserve chromosome stability. There are currently two major projects underway, one that deals with sunlight-induced melanoma, another that is studying a BRCA1- and TopoII-dependent decatenation G2 checkpoint. The melanoma program is an inter-disciplinary, multi-disciplinary collaboration among basic and clinical researchers to develop a systems biology model of sunlight-induced melanomagenesis. The work is funded by two new grants from NIEHS, an R01 to Marila Cordeiro-Stone and a P01 to William Kaufmann. Projects under Dr. Kaufmann’s supervision include analyses of G1 and G2 checkpoint responses to UV in human melanocytes and melanoma lines, analysis of the mechanisms of induction of allelic deletions at the CDKN2A locus in UV-damaged melanocytes and application of microarray technology to distinguish melanoma metastases that are confined to lymph nodes from those that have reached visceral sites. The decatenation checkpoint work is funded by an R01 grant from NCI. This project is working to determine the genetic requirements for G2 delay when sister chromatid decatenation is blocked or slowed, and the mechanisms whereby catenated chromatids signal to block activation of Plk1 and entry to mitosis. Defects in the decatenation checkpoint have been observed in bladder and lung cancer cell lines suggesting that the checkpoint may contribute to maintenance of genomic stability and suppression of carcinogenesis. Human and mouse stem cells have also been shown to display a defect in this checkpoint and the defect is associated with high rates of uniparental disomy as a potentially diagnostic index of genetic instability. We would like to determine the degree to which defects in the decatenation G2 checkpoint contribute to genetic instability in breast cancer and to multistep malignant progression.