Hypermutation in bacteria and other cellular systems

Abstract

A temporary state of hypermutation can in principle arise through an increase in the rate of polymerase errors (which may or may not be triggered by template damage) and/or through abrogation of ¢delity mechanisms such as proofreading and mismatch correction. In bacteria there are numerous examples of transient mutator states, often occurring as a consequence of stress. They may be targeted to certain regions of the DNA, for example by transcription or by recombination. The initial errors are made by various DNA polymerases which vary in their error-proneness: several are inducible and are under the control of the SOS system. There are several structurally related polymerases in mammals that have recently come to light and that have unusual properties, such as the ability to carry out`accurate' translesion synthesis opposite sites of template damage or the possession of exceedingly high misincorporation rates. In bacteria the initial errors may be genuinely spontaneous polymerase errors or they may be triggered by damage to the template strand, for example as a result of attack by active oxidative species such as singlet oxygen. In mammalian cells, hypermutable states persisting for many generations have been shown to be induced by various agents, not all of them DNA damaging agents. A hypermutable state induced by ionizing radiation in male germ cells in the mouse results in a high rate of sequence errors in certain unstable minisatellite loci; the mechanism is unclear but believed to be associated with recombination events.

Hypermutable bacteria isolated from humans – a critical analysis

“…It is of particular interest to note that, in a large collection of E. coli, an inverse relationship has been demonstrated between constitutive mutation frequency and the induction of increased mutation frequency in ageing colonies (Bjedov et al, 2003). A number of reviews discussing stress-induced mutagenesis, both in general and in relation to antibiotic resistance, have been published recently by others (Blazquez, 2003;Bridges, 2001;Chopra et al, 2003;Foster, 2005;Rosenberg et al, 1998).…”

Sixty Alleles of the ALS7 Open Reading Frame in Candida albicans: ALS7 Is a Hypermutable Contingency Locus

“…The genes encoding these proteins have been termed 'hypermutable contingency genes', and the major mechanism underlying the protein variability is rearrangement of repeat-containing parts of their ORFs (Duncan et al 1991;Moxon and Thaler 1997;Barry and McCulloch 2001;Bridges 2001). ALS7 meets the criteria for hypermutable contingency loci in that (1) it is part of a family of surface proteins (Hoyer 2001), (2) it contains repeat units which make it potentially highly mutable, and (3) rearrangement of conserved units in repeat regions generates allelic diversity far in excess of the diversity in both nonrepetitive parts of the ALS7 ORF and far in excess of the diversity reported for other C. albicans ORFs (Bougnoux et al 2002).…”

“…The resulting repertoire of phenotypes is believed to assist in the survival of the organism by allowing it to rapidly respond to, and exploit, alterations in unpredictable and/or hostile environments (Duncan et al 1991;Moxon and Thaler 1997;Barry and McCulloch 2001;Bridges 2001). In the pathogens Giardia, Plasmodium, and Trypanosoma, the biological role of hypermutable surface proteins has been the subject of considerable study.…”

“…The term "hypermutable contingency genes" was coined for such genes (Duncan et al 1991;Moxon and Thaler 1997;Barry and McCulloch 2001;Bridges 2001). Aside from encoding cell surface proteins, hypermutable contingency genes are defined by (1) being potentially highly mutable, and (2) mutations which are not caused by error-prone DNA replication but are rather specific, being brought about by recombination (or methylation) events, involving oligonucleotide repeats or homoploymeric tracts (Moxon and Thaler 1997;Bridges 2001). ALS7 would be particularly well suited as a hypermutable contingency gene in C. albicans; its ORF contains not only the tandem repeat domain, characteristic of all ALS genes, but in addition a second repeat region, the so-called VASES region.…”

Bacterial hypermutation: clinical implications

“…Low migration rates in chronic infections could contribute to increased in situ selection of strong mutator alleles. The function of this hypermutable state could be to generate variability under stressful conditions rather than to enhance survival per se (Bridges, 2001). Do successive antibiotic treatments and/or prolonged antibiotic treatment increase acquisition of antibioticresistant bacteria?…”