Notes on Genetic variability

 Friedberg, Walker and Siede, “DNA Repair and Mutagenesis” 1995

“Once it was recognized that DNA is the informationally active chemical component of essentially all genetic material (with the notable exception of RNA viruses), it was assumed that this macromolecule must be extraordinarily stable in order to maintain the high degree of fidelity required of a master blueprint.  It has been something of a surprise to learn that the primary structure of DNA is  in fact quite dynamic and subject to constant change.  For example, gene transposition is a well established phenomenon in prokaryotic and eukaryotic cells.  In addition to these larger scale changes, DNA is subject to alteration in the chemistry or sequence of individual nucleotides.”

The book out lines the process by which DNA participates in a constant cycle of damage and repair.

>  No genetic alteration is external or random, because alteration is not due to random damage or replication error as much as it is due to a particular type of response to DNA damage.

The book describes 3 types of cellular responses to DNA damage (including errors):  Reversal, excision and tolerance.  The first is a reaction to fairly minor damage which can be repaired  by the action of a single polypeptide enzyme.  Excision is a much more elaborate process by which the damaged or mismatched pieces are cut away and the original sequence is restored.  Tolerance mechanisms do no remove the primary damage and thus often results in a permanent change in the genome.

There are at least 4 known mechanisms for reversing different types of DNA damage, the simplest of which is called photoreactivation of DNA by which a light activated enzyme removes the type of damage that is most commonly caused by UV radiation.

Heterogeneity of excision repair chapter 7
    Because some of the repair mechanisms are tied to the transcription process, there is a bias towards the repair of transciptionally active DNA sequences.  But the existence of repair mechanisms for nonactive DNA has been shown to be of critical importance to the prevention of cancer.

>This pheonmena of  “heterogeneity of exicision repair”  is another example of how the whole process is anything but random.

Mismatch repair chapter 9

Tolerance chapters 10-12
“For example, prokaryotic cells have evolved mechanisms for repairing single-strand gaps and double-strand breaks in their DNA that have arisen either directly from DNA damage or indirectly as the result of processing of the initial DNA damage.  These mechanisms involve proteins that also play roles in the homologous recombination of undamaged DNA.  Niether of these processes appear to be particulary mutagentic.  In addition, prokaryotic cells have evolved another class of mechanisms for processing damaged DNA which, although not yet fully understood a biochemical level, appears to involve the polymerization of DNA past a lesion and is often referred to a translesion DNA synthesis.  In contrast to other systems that act on damaged DNA, this type of processing can be highly mutagenic and, in fact is required for most UV radiation and chemical mutagenesis.” pg 407

 “In the case of E coli, in which these alternative mechanisms for dealing with damaged DNA have been studied most closely it has become clear that their regulation and operation is intimately related to the complex SOS regulatory network.  The expression of the more than 20 genes in this network is induced by DNA damage and is regulated by the LexA and RecA protiens.”  pg 407

The book described the experiements, “that first suggested that an inducible system is required for mutagenesis,”  where UV radiation failed to induce mutation in bacteriophages unless the host cell was also irradiated thereby activating the SOS system of the cell that allowed the translesion DNA sythesis process to occur in the DNA of both the host cell and the invading viral DNA.  pg 466

“Studies of UV radiation-induce mutagenesis of the bacterial chromosome played a key role in the development of the notion that recA+ -lexA+-dependent functions are required for the specialized processing of damaged DNA that gives rise to mutations and that this process is inducible.  Evelyn Witkin’s observation that lexA(Ind-) mutants were not mutable by UV radiation led her to postulate that the lexA+ gene might encode or control a new or modified DNA polymerase capable of inserting nucleotides oposite UV radiation lesions and that UV mutagenesis occurred by a mechanism of translesion replication.”  pg 467

> So we have a set of genes for the express purpose of  of bypassing the DNA repair system to allow mutations to occur!
 

Edward A. Birge, “Bacterial and Bacteriaophage Genetics”

“Transposons are units of DNA that move themselves from one DNA strand to another or to a new position on the same molecule, inserting at nearly random positions.  They are also capable of catalyzing DNA rearrangements such as deletions or inversions.” pg 80.

“One of the basic tenets of genetics is that indiscriminate exchange of genetic information is disadvantageous to a species.  In eukaryotic cells, problems with chromosome pairing during mitosis and meiosis often prevent cells that have acquired foreign chromosomes from surviving.  However, because segregation of the nucleoid in prokaryotic cells requires no such elaborate mechanism, other strategies must come into play.  In particular, many bacterial cells and their viruses use a system of restriction and modification to tag their own DNA and disrupt any foreign DNA that may be present.”