William K. Kaufmann, PhD

My current research is focused on definition of the pathways of DNA metabolism that preserve genetic stability in normal human cells, and elucidation of the mechanisms whereby single genetic alterations perturb homeostasis within and among these pathways. Model systems include primary and secondary cultures of human fibroblasts, lymphocytes, and mammary epithelial cells with defined genetic defects (mutations in ATM or p53). Pathways of DNA metabolism under scrutiny include nucleotide excision repair, double-strand break rejoining, repair of chromatid breaks, post-replication repair, replicon initiation, replicative chain elongation, chromatid decatenation, telomere length maintenance, and cell cycle checkpoints that respond to DNA lesions. Dr. Kaufmann's research program is detailing the alterations in these pathways of DNA metabolism that occur in diploid human fibroblasts that have lost ATM and p53 function, charting the destabilization of chromosomes that accompanies, or is a consequence of, these alterations, and searching for other genetic alterations that induce similar phenotypes. The goal of this work is to define the phenotypes of pre-malignant precursor lesions and develop in vitro technologies to search for pharmaceuticals that suppress growth and stabilize the genome in these precursors.  

Selected Publications:

Kaufmann, WK, Behe, CI, Golubovskaya, VM, Byrd, LL, Albright, CD,  Borchet, K,  Presnell, SC, Coleman, WB, Grisham, JW and Smith, GJ. Aberrant cell cycle checkpoint function in transformed hepatocytes and WB-F344 hepatic epithelial stem-like cells. Carcinogenesis 22: 1257-1269, 2001.

Deming, PB, Cistulli, CA, Zhao, H,  Graves, P, Piwnica-Worms, H,  Paules, RS, Downes, SC, and Kaufmann, WK, The human decatenation checkpoint. Proc. Natl. Acad. Sci. USA, 98: 12044-12049, 2001.

Cordeiro-Stone, M, Frank, A, Bryant, M, Oguejiofor, I, Hatch, S.B., McDaniel, LD and Kaufmann, WK. DNA damage responses protect xeroderma pigmentosum variant from UVC-induced clastogenesis. Carcinogenesis, 23: 959-966, 2002.

Deming, P, Flores, C, Downes, S, Paules, R, and Kaufmann, W. ATR enforces a topoII-dependent G2 checkpoint via inhibition of polo-like kinase I. J Biol Chem, 277: 36832-36838, 2002.   

Kaufmann, WK,  Campbell, CB, Simpson, DA, Deming, PB,  Filatov, L,  Galloway, DS,    Zhao, XJ,  Creighton, AM, and  Downes, CS. Degradation of ATM-independent decatenation checkpoint function in human cells is secondary to inactivation of p53 and correlated with chromosomal destabilization.  Cell Cycle 1:  321-330, 2002.

Heffernan, T, Simpson, DA, Frank, A,  Heinloth, A,  Paules, RS,  Cordeiro-Stone, M and Kaufmann, WK.  An ATR-dependent S checkpoint  inhibits replicon initiation following UVC-induced DNA damage.  Molec. Cell. Biol. 22: 8552-8561, 2002 .