Theoretical investigations on oncogene activation by chemicals and antioncogene inactivation by radiation.

To activate the cancerous genetic information in the cell one has either to activate oncogenes or to inactivate antioncogenes (cancerous growth suppressing genes). These processes usually happen in the cell with the aid of external factors, especially chemical carcinogens' and radiations. It was shown with the aid of simple statistical considerations that both oncogene activation by chemical carcinogens and the double strand breakings due to ionizing radiations leading to antioncogene inactivation most probably are caused not only by local effects. Different mechanisms (like the change of the tertiary structure, the change of the dispersion and polarization forces between DNA and proteins due to charge transfer and different solution mechanisms) were investigated to prove the role of long-range effects of carcinogens in initiating the malignant transformation of an eucaryotic cell.

Long-range effects of direct-hit ultraviolet and particle radiation in oncogene activation.

A simple statistical analysis shows that the oncogene-activation effect of chemical carcinogens cannot be explained if one takes into account only short-range effects. As one of the most probable solid state physical long-range effects, the generation at the site of carcinogen binding of travelling solitary waves, which can interfere with DNA-blocking protein interactions, is discussed. It has been shown that the direct hit carcinogenic effects on DNA by ultraviolet--or particle radiation can also be explained by the generation of solitary waves (in the latter case the first step is a collective plasma oscillation which decays to individual local excitations and ionizations).

Electronic structure of proteins and DNA: solid-state aspects.

The generalization of the Hartree-Fock method to periodic systems (polymers or crystals) using a linear combination of atomic orbitals (LCAO) makes it possible to calculate ab initio self-consistent-field LCAO band structures of periodic protein and DNA models. The results obtained for polyglycine, polyalanine, and for the mixed poly(Gly-Ala) periodic chain, as well as for the four homopolynucleotides, are presented. The correction of these band structures for excitonic effects (in the excited state) and for long-range correlation effects is shown also. Furthermore, it is outlined how the short-range correlation in insulator biopolymers and correlation effects in proteins with a partially filled valence band (for instance, due to charge transfer) can be calculated. The Coherent Potential Approximation is outlined and its possible application to aperiodic proteins and DNA is pointed out. Finally the effect of an electron acceptor on proteins or of a chemical carcinogen bound to DNA is discussed as a local perturbation of the band structures of these systems on the basis of the self-consistent resolvent method.

Physical mechanisms of the activation of oncogenes through carcinogens.

In the last years about twenty human oncogenes have been discovered. It is shown that their main activation mechanisms: through non Watson-Crick-type point mutation, through activation by LTR binding to the end of an oncogene and through transposition of an oncogene to another chromosome need an external agent. The principal mechanisms of short- and long-range effects of chemical carcinogens are reviewed. A possible very effective mechanism for long-range effects of chemical carcinogenesis through generation of conformational solitons in DNA are discussed in detail.