DF/HCC Program Affiliation

Cancer Cell Biology

Research Abstract

Free radicals such as superoxide and nitric oxide (NO) occur as spontaneous metabolic by-products or as cytotoxic weapons of the immune system. We are investigating how these agents elicit specific genetic responses, and the cellular mechanisms that defend against them. The redox-sensing SoxR protein of E. coli is directly activated by free radical signals and provides an important model. NO activates resistance pathways in human cells, but the regulatory proteins remain to be identified. We are investigating the role of heme oxygenase-1 in the defense, and the modulation of apoptosis and survival pathways. A distinct mechanism stabilizes heme oxygenase-1 mRNA in response to NO and is under investigation, as is the general role of mRNA stability in the response to NO. A third area of interest concerns the mechanisms and roles of human enzymes that repair oxidative DNA damage. The human abasic endonuclease Ape1 lies at the intersection of several pathways, processing the products of various DNA glycosylases and acting directly on many oxidative products in DNA. Our studies of Ape1 include: (i) the recognition and cleavage mechanism of the protein for specific DNA damages; (ii) the interaction of Ape1 protein with other repair components; (iii) the regulation of Ape1 expression in response to cytotoxic agents and during the normal cell cycle. Finally, a major oxidative lesion in DNA, 2-deoxyribonolactone, can form protein-DNA crosslinks during attempted DNA repair, and we are investigating how cells process these crosslinks or avoid their formation using alternative repair pathways.

Publications

• Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu JT, Hong AL, Ford E, Cheng HL, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger M
  16439206
• McLaughlin LM, Demple B.Nitric oxide-induced apoptosis in lymphoblastoid and fibroblast cells dependent on the phosphorylation and activation of p53.Cancer Res 2005 Jul 15;65(14):6097-104.
  16024610
• Koutsolioutsou A, Peña-Llopis S, Demple B.Constitutive soxR mutations contribute to multiple-antibiotic resistance in clinical Escherichia coli isolates.Antimicrob Agents Chemother 2005 Jul;49(7):2746-52.
  15980345
• Fung H, Demple B.A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells.Mol Cell 2005 Feb 4;17(3):463-70.
  15694346