N-terminal and core-domain random mutations in human topoisomerase II α conferring bisdioxopiperazine resistance

AbstractRandom mutagenesis of human topoisomerase II α cDNA followed by functional expression in yeast cells lacking endogenous topoisomerase II activity in the presence of ICRF-187, identified five functional mutations conferring cellular bisdioxopiperazine resistance. The mutations L169F, G551S, P592L, D645N, and T996L confer >37, 37, 18, 14, and 19 fold resistance towards ICRF-187 in a 24 h clonogenic assay, respectively. Purified recombinant L169F protein is highly resistant towards catalytic inhibition by ICRF-187 in vitro while G551S, D645N, and T996L proteins are not. This demonstrates that cellular bisdioxopiperazine resistance can result from at least two classes of mutations in topoisomerase II; one class renders the protein non-responsive to bisdioxopiperazine compounds, while an other class does not appear to affect the catalytic sensitivity towards these drugs. In addition, our results indicate that different protein domains are involved in mediating the effect of bisdioxopiperazine compounds

Representations of the discrete inhomogeneous Lorentz group and Dirac wave equation on the lattice

We propose the fundamental and two dimensional representation of the Lorentz groups on a (3+1)-dimensional hypercubic lattice, from which representations of higher dimensions can be constructed. For the unitary representation of the discrete translation group we use the kernel of the Fourier transform. From the Dirac representation of the Lorentz group (including reflections) we derive in a natural way the wave equation on the lattice for spin 1/2 particles. Finally the induced representation of the discrete inhomogeneous Lorentz group is constructed by standard methods and its connection with the continuous case is discussed.Comment: LaTeX, 20 pages, 1 eps figure, uses iopconf.sty (late submission