Professor of Pathology and Laboratory Medicine, UNC-CH
MD/PHD - Washington University
Temporal Activation and Genomic Organization of Functional Origins of DNA Replication &
Endometrial Epithelial-Stromal Interaction in Organogenesis, Homeostasis, and Cancer
Mammalian cells are more susceptible to transformation when treated with chemical carcinogens during the early S phase part of the cell cycle. We wish to explain this vulnerability, and to determine whether DNA replicated during the early S phase might include significant targets for cell transformation. We isolated DNA enriched in sequences that replicated earlier S phase and are now characterizing cloned DNAs with respect to content of earliest replicating DNA, sequence characteristics, and ability to function as origins of replication. We are also assessing clones for nuclear matrix association, since sites of replication initiation and earliest synthesis are thought to be associated with the nuclear matrix. Our long-term goals are to understand the regulation of the onset of the S phase through initiation of DNA synthesis at early origins of replication, and to identify mutations that affect these regulatory regions. We are also studying biologic and molecular features of cancer development in human endometrium using cultured cells. Endometrial epithelial and stromal cells undergo a differentiation in culture and are being combined in culture to reconstruct this tissue. We are investigating how signaling between stromal and epithelial cells determines normal tissue structure and function and how the cells response to steroid hormones. Studies are designed to evaluate the roles of extracellular matrix and the importance of direct cell contact. Endometrial cancer may arise due to disordered signaling between stromal and epithelial cells and this hypothesis is being tested.
- Barbier C, Kloosterboer HJ, Kaufman DG. Effects of tibolone metabolites on human endometrial cell lines in co-culture. Reprod Sci. 2008 Jan;15(1):75-82
- Cohen SM, Cordeiro-Stone M, Kaufman DG. Early replication and the apoptotic pathway. J Cell Physiol. 2007 Nov;213(2):434-9
- Kaufman DG, Cordeiro-Stone M, Brylawski BP, Cohen SM, Chastain PD. Early S phase DNA replication: a search for targets of carcinogenesis. Adv Enzyme Regul. 2007;47:127-38.
- Brylawski BP, Chastain PD 2nd, Cohen SM, Cordeiro-Stone M, Kaufman DG. Mapping of an origin of DNA replication in the promoter of fragile X gene FMR1. Exp Mol Pathol. 2007 Apr;82(2):190-6.
- Cohen SM, Furey TS, Doggett NA, Kaufman DG. Genome-wide sequence and functional analysis of early replicating DNA in normal human fibroblasts. BMC Genomics. 2006 Nov 29;7:301
- Chastain PD 2nd, Heffernan TP, Nevis KR, Lin L, Kaufmann WK, Kaufman DG, Cordeiro-Stone M. Checkpoint regulation of replication dynamics in UV-irradiated human cells. Cell Cycle. 2006 Sep;5(18):2160-7.
- Chastain PD 2nd, Cohen SM, Brylawski BP, Cordeiro-Stone M, Kaufman DG. A late origin of DNA replication in the trinucleotide repeat region of the human FMR2 gene. Cell Cycle. 2006 Apr;5(8):869-72.
Campus Box # 7295
Chapel Hill, NC 27599