Type II topoisomerases (TOP2s) resolve the topological problems of DNA by transiently cleaving both strands of a DNA duplex to form a cleavage complex through which another DNA segment can be transported. Several widely prescribed anticancer drugs increase the population of TOP2 cleavage complex, which leads to TOP2-mediated chromosome DNA breakage and death of cancer cells. We present the crystal structure of a large fragment of human TOP2β complexed to DNA and to the anticancer drug etoposide to reveal structural details of drug-induced stabilization of a cleavage complex. The interplay between the protein, the DNA, and the drug explains the structure-activity relations of etoposide derivatives and the molecular basis of drug-resistant mutations. The analysis of protein-drug interactions provides information applicable for developing an isoform-specific TOP2-targeting strategy.

Investigation of retinal neurochemistry in a well-defined chick model of form-deprivation myopia indicated that dopamine and its metabolite 3,4-dihydroxyphenylacetic acid are reduced in myopic as compared to control eyes. The reduction in retinal dopamine is evident only during light adaptation and is accompanied by a decreased rate ofdopamine biosynthesis. To test whether the alteration in dopamine metabolism is related to eye growth, agents known to interact with dopamine receptors were administered locally to deprived eyes. Remarkably, the expected growth in the axial dimension was reduced, while that in the equatorial dimension was not. Therefore retinal dopamine may participate in the pathway linking visual experience and the postnatal regulation of the eye's growth in the axial dimension. The mechanism for control of chick eye growth in the equatorial dimension remains unknown.Eye growth during normal childhood development coordinates with progressive changes in the optical power of the cornea and lens to maintain image focus on the plane of the retina (1). Observations after unilateral visual deprivation have indicated that retinal image quality influences postnatal growth. Deprivation of form vision in juvenile monkeys (2-4), chicks (5-9), or humans (10-12) disrupts normal regulation and leads to excessive eye size; distant images now focus in front of the retina, causing a myopic refractive error. This link of visual quality to eye size implicates the nervous system in growth control. Moreover, recent observations hint that such control is largely local. (i) Form-deprivation myopia in both monkeys and chicks takes place even after optic nerve transection interrupts the direct pathway from retina to brain (3, 13). (ii) Application of a partial occluder in chicks to restrict vision either in the nasal or temporal visual field induces excessive eye growth only along the corresponding ocular dimension. For example, occlusion of the nasal visual field causes excessive growth of the temporal part of the globe (14-16). We now report in avian myopia that neonatal deprivation of form vision alters retinal dopamine metabolism at the same time as the eye enlarges. Under the identical condition, ocular administration of dopaminerelated agents hinders the expected elongation of the eye in the axial but not in the equatorial dimension. These findings buttress the hypothesis of local growth control and suggest the participation of retinal dopamine in the regulatory sequence. They also speak for separate mechanisms underlying the regulation of axial and equatorial growth of the eye.

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