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LOW-INTENSITY-LOW-DOSE-RADIATION INDUCED GENETIC CODE CHANGES ... LOW-INTENSITY-LOW-DOSE-RADIATION INDUCED GENETIC CODE CHANGES ... Document Transcript

  • LOW-INTENSITY-LOW-DOSE-RADIATION INDUCED GENETIC CODE CHANGES AND THEIR CONSEQUENCES A. Ya. Temkin Department of Interdisciplinary Studies Faculty of Engineering Tel-Aviv University Ramat-Aviv Tel-Aviv 69978 Israel E-mail: temkin@eng.tau.ac.il September 23, 2001 1
  • ABSTRACT Low-intensity-low-dose radiation (ionizing and laser light, as well) and isotope substitutions in chemical groups (adenine, guanine, cytosine and thymine) of the DNA molecule may cause changes in genetic information carried by a DNA molecule when no rupture of its polymer chains occurs. It is shown that in such cases the formal language based on 4-letter alphabet (A-adenine, G-guanine, C-cytosine and T- thymine) must be replaced by another formal language with more than 4-letters alphabet (probably with another grammar). Usually the number of letters in the new alphabet is so large that the use of such a formal language becomes practically impossible and so it would be desirable to avoid the use of a formal language. By this reason it is proposed to use with this purpose the general method of the Ch. 7 of the book [14]. This method allows one to express the physical properties associated with rotational, vibration and electronic states of the DNA molecule and transitions between them in terms of the information and the information processing, correspondingly. Thus, this method is fit for the treatment of low-intensity-low-dose- radiation and isotope substitution biological effects because all properties of the DNA 2
  • molecule and all processes occurring in this molecule are expressed uniformly in terms of the information and information processing. The considered distortion of the genetic information by the low-intensity-low-dose radiation and isotope substitutions is expected to be an important (maybe the main) mechanism being the basis of their biological effects. 3
  • INTRODUCTION In the present paper we consider such kinds of the radiation induced genetic harm that are consequences not of the DNA strand decay [1], but only of such "delicate" damage that leads to distortions of the genetic code. This kind of harm seems to be important at isotope substitution (see, for example, [2-6]) of elements in adenine, guanine, cytosine and thymine groups of DNA molecules, as well as at low- intensity-low-dose ionizing particle, gamma-, X-ray, laser light etc. irradiation. Such distortion of the genetic code even by very low-intensity-low-dose irradiation may lead to a considerable increase of cases of malignant diseases as well as hereditary deviations and abnormalities among the following generations' populations. However, at the same time it may lead to harmful consequences for malicious cells etc., which, possibly, opens the way to low-intensity-low-dose laser and ionizing radiation medical treatment [7-10]. GENETIC CONSEQUENCES OF DNA CHEMICAL GROUPS IDENTITY VIOLATIONS Let us begin from the consideration of the genetic information change provoked by substitution of some elements of adenine, guanine, cytosine and thymine chemical groups of a DNA strand by their isotopes. It is interesting in itself and also will help to understand how to approach to more complicated case of similar effects provoked by the low-intensity-low-dose radiation action. 4
  • The genetic information is written on a DNA molecule by 4-letter alphabet of a formal language. Each letter means one of 4 type chemical group: A denotes adenine, G denotes guanine, C denotes cytosine and T denotes thymine. It is supposed that all chemical groups of the same type are identical. This simplifying assumption allowed one to obtain extremely important and impressive results in the study of genome. However, it must be kept in mind that it is only, so to say, the zero-order approximation to genetic properties of DNA molecules. For example, what is to be happened if nuclei of a certain part of atoms of a certain number of these chemical groups be substituted by their isotopes, e. g., p would be replaced by d in atoms H, i. e., at certain places deuterium will be placed instead hydrogen? This example shows that our question is not only an abstract theoretical question, but is connected with a real situation when the light water is replaced by the heavy water that reaches the DNA in different places substituting hydrogen by deuterium. An isotope substitution breaks the identity of chemical groups of the same type remaining, however, their chemical identity unaffected. Now each two chemical groups are identical when they were not subjected of isotopic substitution or when the substitution (by the same isotope) was at the same place in each group. As a consequence one obtains instead only 4-letter alphabet, the one containing more (maybe much more) letters: the 4 letters existed from the beginning plus letters representing chemical groups (chemically the same as mentioned above, but isotope substituted) classified according substituting isotopes and their places in chemical groups. The information written by this new alphabet forms the new genome. It is important that the considered effect differs profoundly from the kinetic isotope effect, well known in many fields of chemistry. The kinetic isotope effect 5
  • depends on the mass and spin of the element that is substituted by its other isotope, it decreases when the mass number of this element increases. For example, it can be important for the hydrogen substitution by deuterium, but negligible for the oxygen-16 substitution by oxygen-18. In distinct, the considered effect produced by the genetic code change at the isotope substitution does not depend on mass and spin of substituted and substituting isotopes of a certain element. Let us consider the simplest example when in a number of thymine groups CH3 is replaced by CH2D. Denote the corresponding letter TD. Now there is the five- letter alphabet Σ5 = {T, TD, A, C, G}. The formal language built on the grounds of this alphabet will be a new one. The genetic information written on the non-deuterated DNA molecule by the language with the alphabet Σ4 = {T, A, C, G} can be rewritten by the new language with the alphabet Σ5 = {T, TD, A, C, G}. Then the information carried by a non-deuterated and deuterated (as it was described) DNA molecule will be written by the same language with the alphabet Σ5 = {T, TD, A, C, G}. It allows one to compare the genetic information in these both cases, and by this way to understand to what genetic changes leaded this isotope substitution and at what degree these changes are important. It is correct also, if not the whole DNA molecule is considered, but only one gene. Whether a copy obtained by the duplication of a deuterated DNA molecule could be deuterated? This is a very important question for the genetics. There are two possibilities: 1) the copy will not be deuterated, in general, and 2) the copy may be deuterated by the H - D exchange with the original deuterated DNA molecule or the protoplasm. It is very not probably that in the case (2) the deuterium substitution will occur namely at the same places of the new DNA molecule than it was on the original one. In other words, the identity of the initial DNA molecule and its copy in that what 6
  • concerns the isotope substitution places, practically is not accessible. This means, the genetic information carried by the copy (written by 5-letter-alphabet language) will be not the same that the one carried by the original molecule. Really, the situation is even more complicated because the new alphabet may contain more than five letters. Indeed, the substitution of H by D is a stochastic process and so can occur not only in CH3 of thymine, but also in other places of thymine and even in other three types of chemical groups. It creates more than 5 types of groups distinguished from the original ones and between themselves, which means that the new more than 5 letters alphabet and, therefore, the new formal language will be created. In the case (1) the new DNA molecule will not be deuterated and, therefore, all the following generations of DNA obtained by subsequent duplications will be not deuterated. However, it is correct only, if in a certain generation of DNA molecule the isotope exchange with the protoplasm does not occur. Thus, the influence of the deuteration will be ended at the initial generation. As opposed to this, in the case (2) it will remain for all generations. It is to expect that the case (2) will be realized when the protoplasm contains deuterium. For example, drinking the heavy water can create such a situation. GENERAL CASE The chemical identity of deutero-substituted and not substituted groups really was not used in the written above. As a consequence, the similar consideration would be valid also in the case of radiation- and photochemical processes occurring with DNA molecules. It opens a way to the consideration of such "delicate" genetic effects of low-intensity-low-dose ionizing radiation or light, when only a number of chemical 7
  • groups in a DNA polymer chain were changed, while the polymer chain itself is not decayed. Such situations may arise in radiation and photobiology. Then ionizing radiation or light, e. g., laser light, may induce, for example, one atom H abstraction from CH3 group of thymine in a number of places of a DNA strand. Thymine groups with CH2 instead CH3will be different from those with CH3. From the point of view of formal language it will be the same case than the substitution of CH3 by CH2D, and, therefore, all written above remains valid. Of course, changes that are results of the formal language changes do not exhaust all changes of the genetic information produced by this reaction of the H atom abstraction. This means, when one considers genetic changes produced by irradiation, it is to divide them into those based on the formal language change and those based on changes of physical and chemical properties of DNA molecules. Their dependence on the type of radiation, dose and dose rate may be different. The first type is especially important at low dose and low dose rate. Indeed, it is enough a few of cases of the chemical group identity breaking to provoke serious hereditary aberrations of the future generations or such diseases as, for example, cancer of the irradiated person himself. The realization of different effects, arising as consequences of the chemical groups' identity breaking, depends essentially on the value of the information [11-13] carried by the DNA molecule or by its segments where this identity breaking occured. The situation is expected to be much more complicated than the described above, when the identity breaking of chemically identical groups occurs by "labeling" a certain part of them by nuclear spin inversions or excitations of molecular quantum levels. In such cases this "labeling" is rapidly changed as function of time (notice that isotope exchange may also lead to the time dependence of the "labeling"). Under such condition the new alphabet must contain an enormous number of letters and the "text", 8
  • i. e., the genetic information, would be rapidly changed as function of time. In such a situation the writing of the genetic information by a certain formal language becomes impossible. As a consequence of this fact the new question arises: what, in general, is in such a situation the genetic information, in other words, how this concept can be defined, and under what conditions this concept is not nonsense? A criterion that this concept is not nonsense is as follows. Let I0 is the amount of the genetic information carried by the original DNA double helix, and ∆I is the maximum change of this information amount provoked by different factors, as it is written above. Let ∆I reaches its maximum in time τ. Denote θ the characteristic time of life of a DNA strand from its appearance up to its duplication. Then the concept of the genetic information has meaning, if ∆I << I 0 , or, when this inequality is not fulfilled, if τ>>θ. In fact, this criterion is not enough, and a number of other criteria must be found that take into account not only the amount, but also different components of the genetic information and their values. For example, the criterion written above may be fulfilled, but at a certain segment of the DNA strand, e. g., a certain gene, the local change of the information would be too large and would reach its maximum in too short time. Then a gene (or genes) may be distorted or destroyed. The criterion can be rewritten as follows. Let L denotes a segment of the DNA strand. Then one can introduce local information amount and its change, as well as the corresponding time necessary to reach the maximum of this change: I0,L, ∆IL and τL, correspondingly. It must consider the set {L} of all possible segments covering the considered DNA strand, and to formulate the above written criteria for each L: the concept of the genetic information has meaning, iff for all L be ∆IL<<I0,L, or, when this inequality is not fulfilled, iff for all L be τL>>θ. Possibly, there are other criteria that take into account the values of information [11-13] carried by segments. However, we have used "iff" because the task 9
  • to determine values of different types of genetic information is extremely difficult, complicated and not clear, and we shall not consider it in this paper. What means "all possible segments"? It is not arbitrary set of any segments, but that taking into account their genetic meaning. One possibility is that each segment must be a gene or its part, or a number of whole genes, but cannot consist of a part of a certain gene and a part of its neighbor one. If some factors provoke changes of the information carried by DNA double helix, as it was explained above, but the criteria written above are satisfied, the concept of the genetic information is not nonsense and it is to search for a relevant method of its expression. It is evident that the use of an alphabet expanding simultaneously with a corresponding change of the formal language grammar would be not practical. It must search for other methods. GENERAL METHOD Physical processes occurring when an excitation propagates through a DNA molecule can be expressed in terms of information and information processing, as it was done in the general form in Ch. 7 of the book [14]. In this chapter the method of the information processing by activated chains of relations (ACR) [ 14, Chs. 1-3] is applied to the molecular genetics. Try to discuss whether it is fit for the considered problem. Each chemical group a of a DNA molecule has a number of quantum states µ . Consider a certain chemical group a in a state µ as a special entity a µ and represent 10
  • the group a not as a chemical group in different states µ , but as the set a = { a µ } . Note that in the case of isotope substitution µ labels the considered chemical group substituted at certain places by certain isotopes; one value of µ labels this chemical group without substitution. This pure formal change of notations (which does not affects the meaning) allows one to apply the method of the book [14] to the considered problem. All such elements a = a µ{ } of a DNA molecule form a set AS = { a} . If AS = { a} be ordered [14, §7.1], it is none other than the source set defined in [14,Ch.1]. If the ordering throughout the DNA molecule is impossible, it is to divide it into a number of segments such that each segment could be ordered independently of others [14, Ch. 7]. After the set AS = { a} was ordered the mathematical formalism of [14, Chs. 1-3 and 7] can be applied to the considered problems. Note that a µ may be not only different quantum states (vibration, rotational, electronic), but they may be ionized states, states when one (or more) atom was abstracted from the group, isotope substituted group etc.. Therefore, the theory of Ch. 7 of the book [14] can be applied to a DNA molecule subjected of isotope substitution, excitation of its different degrees- of-freedom, ionization, atom abstraction etc.. In the majority of cases of low-intensity- low-dose laser irradiation only the excitation of rotations, however, some times (it depends on photon energy) also excitation of vibrations and electronic levels is to be taken into account. In the case of low-intensity-low-dose-ionizing-radiation action upon DNA molecule also the excitation of electronic levels and ionization customarily must be taken into account. The theory proposed in [14, Ch.7] leads to the new definition of the gene that includes not only the information expressed by the genetic code, but also the 11
  • information carried by nuclear and electronic motion in DNA molecule. In the book [14, Ch. 7] the gene defined so is called C-GENE (complete gene). Its part that does not include the information written by the genetic code is called S-GENE (soft gene). The s-gene expresses in terms of the information and information processing the physical properties and processes on the levels of nuclear and electronic motion of the DNA molecule. This is comfortable for the consideration the influence on genetics, for example, the excitation of rotations, vibrations or of electronic levels by the irradiation. CONCLUSIONS In the present paper we consider the role of the genetic information distortion without DNA molecule rupture by the low-intensity-low-dose-laser- or ionizing radiation as well as by isotope substitutions of elements in DNA molecule in biological effects produced by these factors. It was shown that the approach based on the use of formal languages could be realistic only for the several simplest cases of isotope substitution. Namely, when new formal languages with the number of letters in alphabet more then 4, but not large, should be used instead the usual 4-letters one (A - adenine, G - guanine, C - cytosine and T - thymine). However, usually the consideration of the isotope substitution demands the use of formal languages with too large number of letters in the alphabet that makes the use of this approach practically impossible. For the consideration of effects created by the irradiation the number of letters in the 12
  • alphabet of the relevant formal language may be so large that practically should be consider as infinite. We proposed to use for the treatment of the considered effects the method of the information representation and processing by DNA molecule described in Ch. 7 of the book [14], which is based on the corresponding general method of Chs. 1-3 of this book. This method allows one to express physical properties and processes of a polymer molecule, e. g., DNA, in terms of the information and information processing. Then these properties and processes can be included into the common framework with the genetic information written by the genetic code. As a consequence of this the concept of gene was extended [14, Ch. 7] so that it includes, in particular, the dynamics produced by physical processes occurring on the levels of intramolecular nuclear and electronic motion (transitions between rotational, vibration and electronic states of the molecule). This representation is fit for the consideration of the genetic information radiation damage because it is homogeneous and does not demand the "sewing together" such heterogeneous characteristics as those expressed in terms of the genetic code and those expressed in terms of physical properties and processes. Probably, the described mechanism based on the genetic information distortion is essential for biological effects produced by low-dose-low-dose rate-radiation. However, it must be taken into account that other physical, biochemical and biological mechanisms also contribute to these effects and cannot be neglected. 13
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