DNA Maintenance and its Relation to Human Pathology

The evolution of life bears witness to the pliability of DNA. This molecule has changed and diversified not simply by base changes but also by duplication and expansion of coding and non-coding sequences, reshuffling of elemental units of function and interaction of segments by processes that involve DNA repair functions. Furthermore, as the genomes increased in complexity and, redundancy, in the form of di-or poly-ploidy, became the rule, the transmission of genetic information from one generation to the next had to rely on regular processes of matching, reassorting and segregation (i.e. meiosis and sexual reproduction), which also require DNA repair. Such repair, therefore, is an essential part of life in its widest possible sense. Commonly, however, DNA repair is seen as a process that ensures correct DNA copying and forms a last line of defence by reversing or removing damage that the cell has failed to prevent.DNA repair functions are present in virtually all organisms either as corrective activities in DNA polymerases or as independent enzymes or both. Thus, for example, a small genome, bacteriophage T4, which relies on host cell functions for its expression, codes for its own pyrimidine dimer repairing enzyme. This stresses the importance of DNA repair and suggests that individual solutions may be required to optimize its adaptive value. In fact if the survival of a species depends upon the ability of its genome to adapt to changing environments a fine balance must exist between the forces that stimulate and those that suppress DNA change. Therefore, the DNA repair processes of different organisms should vary in detail even if they follow the same schemes dictated by both the structure of DNA and the environmental agents that have acted on DNA during evolution. Furthermore, in higher organisms one can distinguish germ line and soma. The former, immortal and responsible for the propagation of the species, may need special devices to maintain its DNA.In the last 20 years an enormous amount of information has been published on the DNA repair of different organisms and especially Escherichia coli and man. Many reviews of different aspects of this topic are available, but Friedberg (1985) has most impressively waded through existing information to provide a comprehensive, critical and extremely clear picture of DNA repair in both prokaryotes and eukaryotes. I shall consider the role of DNA stability in human pathology. Space, however, does not allow a complete and systematic review. I shall therefore present a personal view.DNA is subject to both spontaneous degradation and exogenous damage. The former, which comprises base loss, base deamination, and strand breakage at sites of base loss, is due to the instability of the components of the DNA molecule and is easily repaired except for the deamination of 5-methylcytosine to thymine, which may cause hotspots of G to A transitions (Lindahl & Nyberg, 1972, 1974; Lindahl & Karlstrom, 1973; Lindahl, 1979; Coulondre et al. 1978). Spontaneous DNA damage may also result from attack by endogenous reactive chemicals produced during cell metabolism, such as oxygen radicals. Reactive oxygen species are known to occur in mammalian cells.. Thus, for example, singlet oxygen has been demonstrated in both the lens and retina of the mammalian eye. Superoxide radicals (O2”) are formed by single electron addition in almost all aerobic cells and stimulation of some cells (phagocytes) may lead to bouts of O2- production as part of normal physiological 1978). electron addition the or to by et al. that of are produced of in from In the of or O2- may the reactive radicals at the of and are reactive and may from of however, may the cell through special and radicals may and this may especially in the of a that and radicals. from by & 1979; may or or in the of some or the of some mammalian cell & The amount of DNA damage by the endogenous species is cells are in and and the most are in and but is that the between generation and can be spontaneous DNA are due to of during DNA In of is in to one in to base and by DNA polymerases this to to to and, repair to et al. of in are DNA polymerases not have functions and therefore may a to in et al. that in that by at a of to that this result by an independent and that a must to the to the to in may also be by both and environmental which cause a of for a spontaneous and DNA damage is repaired by or the of a single and is or of the of pyrimidine the repair of and oxygen by & & Lindahl, et al. the of the of sites & & In the importance of and is and the of strand is possible in the of that have is however, that the of is the of agents is to the oxygen in of cells not repair not and are to or agents et al. et al. repair has but and are by the of a for and have been The of by a different in an formed by the of the and on both of the and or of pyrimidine DNA repair the and the of the DNA In to be in the of this repair but its is DNA polymerases and to to DNA repair and form of may complete repair & Lindahl, mammalian cells are of repair as by in which they are DNA. example, et al. of at and or independent of or of DNA repair in must consider the of and is the of different DNA may be both by the DNA and the repair is by the of and the of the and structure is during repair & et al. Furthermore, an that is in repair that is not repaired DNA may by or result in the of DNA and cell are damage that to the of DNA and a to repair. such in human cells are is DNA damage repair or for is to DNA repair in to not this the to a DNA repair but also is the one The and cell aspects of the have been al. 1979; & is an an of in by and of the and damage to the eye. of the are due to and or and A of of the the of the are in repair the in DNA and are is to have been and et al. 1972, 1974; et al. et al. 1979; et al. 1979; et al. et al. and are the most in and A is the most in The of A a those of have such and those of to of a et al. 1974; et al. comprises and one also a et al. 1979; et al. & different G et al. 1979; al. & and are by single those of et al. 1974; et al. and I is by et al. The cells of from all have been to have clear in DNA repair of sites to for pyrimidine and, of DNA by et al. et al. et al. et al. & 1979; et al. et al. therefore, are in the of pyrimidine and must be in this repair in man. the of such is not may be but also between some of the known may result from and different different This has been for and on cells of one as as they are by normal cells in the of is a function of the of which in the of normal by the interaction of not be the in the at different In the of is present in in normal and to the the of and are not in in the cell not of the and the of the that of the are also of between such et al. & of the have been by the of or which to for the of the et al. et al. of in which are to repair of DNA and the complexity of the mammalian the need of to the repair of in man. Such to form a as by the of a the of pyrimidine in et al. by the for the by the to on the of the pyrimidine dimer by The function of such a may the of the and of the DNA. example, some that may be required to repair of normal cells attack pyrimidine in those of cells from and attack in DNA et al. & repair is in and at the & may also be required to such Furthermore, may different components of the of repair or the of pyrimidine from different of the cells are in the of repair et al. et al. and the of to and & et al. et al. This suggests that some may the repair of in of the cells are to different and to a of This that the of the human DNA is & have that different may have on such Therefore, the picture is of a repair components that may its to the of is DNA repair and of pyrimidine normal but DNA of cells in in of a that can be by of in the et al. The cause of such is not known but be a in for the of DNA damage. and are and cells are to the same Therefore, be to that they have a in such for example, an by cells to DNA damage is in of such an et al. and a have the of a in repair by in cells a of DNA strand breakage during the from and et al. & on the DNA repair of in and of to but a is the of such should have part of this to and and to spontaneous of and to agents have been for and even et al. et al. 1979; et al. et al. et al. et al. have been 1979; & are in and most cell are cells are to the of but DNA repair has been et al. The most of in cells is a of of DNA and et al. 1979; & and this the that of DNA repair may the of has to that cells may be in the repair of DNA. this and of have The that the and involve is by the of of (i.e. and therefore special cells of and the of This is to cause the and of of DNA and also in and, therefore, is to if the are for an or for both an and In fact they in an to the in or In of the of the and the of the is and has not been for the of either have been in cells may to but this is and in et al. et al. & & and some have on the to agents such as and & et al. 1979; et al. et al. of DNA repair have not been but DNA is and to et al. and an of cell in DNA repair has also been & The of cells is of spontaneous and, in the to between at and the of Such are DNA and the which the may also be by at DNA interaction of (i.e. except those of the Therefore, the of by of spontaneous & et al. et al. a that its at DNA of DNA has been & et al. but not in all have changes in the of in either cells or in and have the for or by the cells et al. et al. et al. however, & et al. et al. have a of in cells as the of is from to the of in normal cells is at the physiological of have that at a the in DNA that occur in Such however, also be the of & which that cells oxygen radicals produced during normal In this and the of the of & is on the in of cell or in the of of a by & et al. Such a however, does not the of the of and for the that cells may have at DNA may from the of et al. that the in cells occur (i.e. during the of the to and the DNA This is a in normal cells occur during both DNA of the & et al. and therefore, that the of cells is to of the DNA cells are to the and of and of some in the repair of DNA strand but is of et al. The for a of DNA repair in therefore, on the that the survival of cells does not in to the they are at or in a as to DNA repair of cells is the of DNA and, of & & & et al. This suggests that of in normal cells may be an process of adaptive value. Therefore, has been that of DNA may DNA repair in the of cells to be due simply to the to cells not repair damage in A but suggests that in structure and for the of cells on the of DNA have the of & & as have also et al. cells may breakage and are to the and of agents such as or and to of DNA in the repair of DNA have not been demonstrated et al. et al. 1979; et al. and a of different has been in or have a in the of oxygen radicals on the that the of cells may to oxygen and to or from enzymes that on oxygen radicals & oxygen does not cause DNA breakage in the cells & and the of the of on cell has been & also that this is et al. and the have been as for on the of DNA repair Thus, for example, a in between the of and the to the that DNA damage from endogenous or exogenous is the cause of of for such a in or and in its survival to and in cell from by and et al. et al. et al. et al. and as to that some aspects of the and of the and are by DNA repair and In of this and the of such as and et al. & et al. et al. in of the they is a such to be in a and, at in is not the of the of and to be in and they both are at of normal in some of the they & al. In that the of and is that of This on the and role of the is from the in & et al. et al. et al. that DNA damage is to has on to or forms of have been in some such & cell coli and and the on from different vary both in and Thus, for example, & the to of from cell et al. normal cell survival and the of damage in in to be of and have on et al. & et al. et al. & The of coli and have also a of et al. et al. & et al. et al. et al. et al. to and in from or et al. et al. but the cause of such is not has also been a for that may of DNA repair, and the most in this is a to and of sexual at years of The of this have to agents and a in DNA et al. to agents have been in the of or such for example, and et al. the are in the processes of such and, therefore, the they provide are to be a of the process the of a In fact be that from are not a for the of of DNA repair, they are a cell of and to environmental and environmental to such an in a of as to be to and damage and et al. may also result from the of cell have and may in easily DNA repair functions et al. et al. In the of the of cell in human suggests not of the but also a and a of the that the survival of human cells is to that as to the DNA repair of and to processes that may DNA in a for example, of and of oxygen This the that to does not a of DNA repair or The however, of a in in et al. has not been et al. and the of in et al. is the of radicals as in the and processes to the life of the cell may which may cause endogenous damage the and defence of the cell are of have been in & but the of of oxygen radicals has some in the in its is The of a in has been This on the from cell of a that be by A has also been in higher in and of et al. and in the of such as and The and of is not known as result in reactive of stability to as therefore, a of the the or a of the in and cell in for example, of and the of that also result in radicals and the and are from for the of due to or a in the of oxygen radicals is This is a of that the may not be of or to of and and even to of the The is a a to the as seen in a does not to be a and the if in the in complete changes or and that have on normal cells and cells from such as and Such are and to as to that the cells from damage DNA even DNA breakage is in cells those for et al. et al. In of electron generation of radicals & both and DNA damage. Furthermore, the DNA breakage by in cells is to normal by the addition of units of to the the can be by of the enzyme. Superoxide on the has on DNA breakage and on cell O2- in the which can easily the cell and damage DNA either or the the of such on damage can be to be small & of cells in by normal and, of the cells in by the does not the of either cell that cells not in the et al. have to the for the of The cells of oxygen radicals or and, therefore, radicals cause and damage. This as a and in the of the The by as part of physiological cause damage and a responsible for the of the et al. to a of to reactive oxygen have therefore its on cells and the have been et al. & the have to in complete in a transmission of a of & of the in the DNA repair of is due to possible to and have been as for the of human to provide for the of as between to to DNA such as pyrimidine of et al. and a of in cell and of & the that the of are due to the of single is even if to a of to the of cell and Thus, that both and cells are to the is to also the for the and of on and to the that DNA damage its in a by that and environmental not to human to is the that cells repair DNA by not of repair the role of instability and genetic a cause of single of and is is reviews of the increased of in et al. the of is if consider and that the cells of the are in single they all or and to damage of to and for and also cell In the and may lead to or that and by and the in may result in cells genomes but for as by The importance of such is by in and and et al. et al. to may be and the a of that such be if for the of in this of one the of the required changes to be in The in or the to be a that in is by an that for the in the This has been demonstrated by of and which have that for the may be by or by of the that may be is to in this that from may or may not the of the but the to et al. in to have or and therefore the for a of DNA repair to in and on of of in for and and & Such a of the and to on the of have been et al. and those on and from of the genetic information of the cell or of its and have been as of and, therefore, functions have been at in to this have been of such as and have been for & 1974; et al. et al. et al. et al. et al. in the of some repair functions during the life of different or during the life of cells in have been by & and not provide clear at in for an of DNA repair in or in et al. et al. & et al. between the by and the of mammalian species has been not & 1974; et al. et al. et al. and, in the of of cells from of different species may not repair The that the evolution of non-coding DNA in is in and DNA at in the germ line of but in generation also such an et al. is that some of and both DNA repair in cells and In is known the and of human and, mammalian meiosis and and but this be a of the the of meiosis and by in DNA repair such as those that may exist in for or for DNA metabolism, such to human and by on as by In fact a a higher of and different in the of for and & This and must be by of the germ line and its to stability suggests that special may exist for the of its and has been the possible and of meiosis and et al. the DNA at meiosis and this may Thus, the of and in suggests a higher at meiosis & Furthermore, a of human or in the of have been to at such as therefore, DNA in the to that in are the of and meiosis by DNA and on this is not the of or germ cell in The of the of to and that of the germ line for the which both to at the to cell and generation & 1973; Therefore, the cell be in the germ as germ cells cell to meiosis and germ cells in a of years of & is however, to that in the of and not the is at or cell and be a in the transmission of genetic information the for at the of Such however, not to to the human In to the genetic of The the of the in life and to in the have a DNA and of to one and years Furthermore, of the and, the is at is a germ cell is the normal for the but is of in the & et al. of and may be to maintain the of the genetic the In of both cell and an of germ cells (i.e. at at that during sexual and and therefore germ cell may however, on the by they may therefore on of and especially on the of during the This is but be of is for example, that of and This cause changes in the of to at different in different such In such are of functions be during the between the of meiosis and The the that on a of genetic and to or on a such a process during the life of the especially if the life of this Thus, for example, if one of the of a a to one of the the change. The of if the by from to to should have a of the even if is is that the of are extremely to by & & species in to to also that at the of the if not in & cell as as for and DNA is may the and may a part & however, is the for at is in and therefore should be on I that function is as an of genetic This not function is essential to but also different to that DNA damage be a of the genetic damage by the Thus, the evolution and the repair of to DNA that the DNA damage may the the in DNA during suggests that the of may be in to the of DNA damage et al. 1979; et al. 1974; & et al. The of such vary the of genetic damage and be at damage to the of the in & The of genome and the of be the higher of single in in & is clear that is to the DNA repair of man. of DNA damage the of the may be due to or to damage in small of the to a does not the DNA repair if that is clear not clear DNA repair and to DNA metabolism, may repair and repair of et al. are and to provide and for the of the of DNA human repair enzymes some and have been but of such enzymes have not been the a a is and one is the of its different units and and of the on DNA and repair of such as those that the of and is but is by the of human of by DNA damage or produced in by and are but is & et al. & importance of in the of the of radicals in the of and some agents and the endogenous DNA damage that be by radicals that the for the and of radicals may an role in the of DNA stability and the of have for the of DNA repair in and a for on has to its example, the of and has to the that the the pyrimidine may be a et al. The ability to has the of pyrimidine dimer repair in and mammalian DNA et al. The of and of in both mammalian cells and coli have the of not but also to and DNA repair and both and in mammalian cells et al. & et al. & et al. et al. & et al. et al. et al. et al. the on such exogenous may not those in the normal In fact the DNA damage and degradation and of higher those of importance is the of for the of repair Many such of coli have been and for a in has also been as at DNA repair have been and at et al. & et al. & & et al. et al. & & and, therefore, has the of human DNA repair but a has been This is as segments of human DNA are to a a DNA mammalian cell line a that have and the can be and for to an cell that has by the and of a should human DNA. This can be easily by to for human DNA The human DNA from a cell the of can be by a of DNA is from the cells and by the of a they are to the human DNA of A DNA from such a may be to the human DNA. from such a human DNA can be to or the or DNA and to the DNA to the or In this a human which the to and and the of a cell has been and to et al. et al. of human DNA human cells has not to the of DNA repair as this the of the however, & (1985) have a for the of mammalian that should of the In this should or the due to the complexity of the human genome, the of the human and The has also been to and of the DNA. The in this is the of the for the but of the function and importance of human can be for the are therefore, that a to the is the of or that are of in of the of human cell of DNA repair that can be as of mammalian repair The of human repair to the of human DNA repair and its importance be clear are the that be from such to the genetic of DNA repair and to the of to to if a DNA repair had been and if of and available, they be to follow the segregation of in and to at a of the or in the this in the genetic of such as and the of is at a the of a for the same is on the is of a at have a in of an are for such et al. 1974; et al. et al. et al. et al. but the of the segregation of DNA be a also be the of for DNA repair if to of DNA on the of