Better living with hyper-mutation.
The simplest forms of mutations, base substitutions, typically have negative consequences, aside from their existential role in evolution and fitness. Hypermutations, mutations on steroids, occurring at frequencies of 10(-2) -10(-4) per base pair, straddle a domain between fitness and death, depending on the presence or absence of regulatory constraints. Two facets of hypermutation, one in Escherichia coli involving DNA polymerase V (pol V), the other in humans, involving activation-induced deoxycytidine deaminase (AID) are portrayed. Pol V is induced as part of the DNA-damage-induced SOS regulon, and is responsible for generating the lion's share of mutations when catalyzing translesion DNA synthesis (TLS). Four regulatory mechanisms, temporal, internal, conformational, and spatial, activate pol V to copy damaged DNA and then deactivate it. On the flip side of the coin, SOS-induced pols V, IV, and II mutate undamaged DNA, thus providing genetic diversity heightening long-term survival and evolutionary fitness. Fitness in humans is principally the domain of a remarkably versatile immune system marked by somatic hypermutations (SHM) in immunoglobulin variable (IgV) regions that ensure antibody (Ab) diversity. AID initiates SHM by deaminating C → U, favoring hot WRC (W = A/T, R = A/G) motifs. Since there are large numbers of trinucleotide motif targets throughout IgV, AID must exercise considerable catalytic restraint to avoid attacking such sites repeatedly, which would otherwise compromise diversity. Processive, random, and inefficient AID-catalyzed dC deamination simulates salient features of SHM, yet generates B-cell lymphomas when working at the wrong time in the wrong place. Environ. Mol. Mutagen. 57:421-434, 2016. © 2016 Wiley Periodicals, Inc.
Department of Biological Sciences, University of Southern California, Los Angeles, California.|Department of Chemistry, University of Southern California, Los Angeles, California.
Myron F
MF
Goodman
D003564:Cytidine Deaminase / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics*; D056084:Genetic Fitness / Q000276:immunology; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008957:Models, Genetic; D009154:Mutation; D059645:Mutation Rate; D013014:SOS Response, Genetics; D027041:Somatic Hypermutation, Immunoglobulin; D013698:Templates, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D029968:Escherichia coli Proteins; D007135:Immunoglobulin Variable Region; C120926:DNA polymerase V, E coli; D004259:DNA-Directed DNA Polymerase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
AID; DNA polymerase; RecA nucleoprotein filament; SOS mutagenesis; hypermutation; immunological diversity; translesion DNA synthesis