Response 1 to 'Smaller role for pol η?'

Rogozin, Igor B.; Pavlov, Youri I.; Kunkel, Thomas A.

doi:10.1038/ni1101-983

Cited by 11 publications

(6 citation statements)

References 8 publications

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“…We did not find a substantial number of A-T mutations, which typically comprise one-half of all SHM [47,58,61]. This result corresponds with earlier published results on the expression of AID in E. coli [24,36], in yeast [48], in murine fibroblasts [13], and in human hybridomas [35].…”

Section: Resultssupporting

confidence: 91%

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Expression of human AID in yeast induces mutations in context similar to the context of somatic hypermutation at G-C pairs in immunoglobulin genes

et al. 2005

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Background: Antibody genes are diversified by somatic hypermutation (SHM), gene conversion and class-switch recombination. All three processes are initiated by the activation-induced deaminase (AID). According to a DNA deamination model of SHM, AID converts cytosine to uracil in DNA sequences. The initial deamination of cytosine leads to mutation and recombination in pathways involving replication, DNA mismatch repair and possibly base excision repair. The DNA sequence context of mutation hotspots at

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Section: Resultssupporting

confidence: 91%

“…Another type of mutation, which comprise about 50% of all mutations during SHM, is a change at the A-T base pairs [47,58,61]. The explanation of the mutation origins in A-T base pair is based on several observations.…”

Section: Discussionmentioning

confidence: 99%

Expression of human AID in yeast induces mutations in context similar to the context of somatic hypermutation at G-C pairs in immunoglobulin genes

et al. 2005

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“…This possibility is consistent with the observation that five of six WA SHM hotspots correlating with the pol sNTS spectrum are flanked by a 5Ј-template G ( Table 5). The idea can also account for the fact that the average number of in vivo mutations in all WA motifs fused with RGYW motifs is greater than in WA sites not fused with RGYW (11,42). The strand bias in mutations in A-T sites would then partly depend on the local concentration and orientation of modified G-C pairs and the distance of putative A-T hotspots from these cytosines in each strand and should vary from gene to gene, which is again what is seen in a larger number of target sequences (30).…”

Section: Discussionmentioning

confidence: 99%

Correlation of somatic hypermutation specificity and A-T base pair substitution errors by DNA polymerase η during copying of a mouse immunoglobulin κ light chain transgene

Pavlov

Rogozin

Galkin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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117

110

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To test the hypothesis that inaccurate DNA synthesis by mammalian DNA polymerase (pol ) contributes to somatic hypermutation (SHM) of Ig genes, we measured the error specificity of mouse pol during synthesis of each strand of a mouse Ig light chain transgene. We then compared the results to the base substitution specificity of SHM of this same gene in the mouse. The in vitro and in vivo base substitution spectra shared a number of common features. A highly significant correlation was observed for overall substitutions at A-T pairs but not for substitutions at G-C pairs. Sixteen mutational hotspots at A-T pairs observed in vivo were also found in spectra generated by mouse pol in vitro. The correlation was strongest for errors made by pol during synthesis of the non-transcribed strand, but it was also observed for synthesis of the transcribed strand. These facts, and the distribution of substitutions generated in vivo, support the hypothesis that pol contributes to SHM of Ig genes at A-T pairs via short patches of low fidelity DNA synthesis of both strands, but with a preference for the non-transcribed strand.H igh affinity antibodies result from somatic hypermutation (SHM) of Ig genes followed by selection. The SHM process introduces base substitutions at a very high rate into DNA encoding the variable regions of immunoglobulins (1-4). Although the mechanism for introducing these sequence changes is currently unknown, several features of SHM specificity offer clues to the DNA transactions that might be involved. For example, SHM primarily occurs in two highly mutable DNA sequence motifs (5-9). One is the RGYW sequence (the underlined G is mutated, R ϭ A or G, Y ϭ T or C, and W ϭ A or T), which is found in SHM substitution spectra in equal proportions in both DNA strands. The other is the WA motif, where substitutions are more likely in one strand than the other (5, 7-10). A clue to the origins of the substitutions in the WA motif is the observation that their type and location correlates with the base substitution error specificity of human DNA polymerase when copying a bacterial gene sequence in a model system in vitro (8). Based on that correlation and additional considerations of the two mutable motifs (11), we suggested that errors at A-T base pairs by pol may contribute to as much as one third of somatic mutations in Ig genes, preferentially during synthesis of the non-transcribed strand. This hypothesis is supported by the observation that XP-V patients lacking active polymerase have a lower proportion of somatic substitutions at A-T base pairs in Ig genes (12). Because pol error specificity does not correlate with substitutions in the RGYW sequence motif, and because those substitutions are distributed equally on both strands, we further suggested that SHM may involve more than one DNA transaction and more than one DNA polymerase (8). This finding is consistent with the two-phase model of SHM proposed earlier (9, 13). Other DNA polymerases suggested to participate in SHM include pol (14-16), pol (17, 18) ...

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“…A correlation between the WA motif and the error specificity of human Pol and lack of A-T mutations in XP-V patients deficient in Pol suggested that this polymerase may contribute to the WA hotspots [114,135,136]. The error specificity of Pol does not correlate with SHM at G-C base pairs in the RGYW sequence motif.…”

Section: Analysis Of Somatic Mutations In Immunoglobulin Genesmentioning

confidence: 99%

“…Somatic mutation hotspots in V regions occur primarily within two DNA sequence motifs. RGYW hotspots [25,114] are found in both strands and WA hotspots preferentially are found in only one strand [25,92,95,114,134,135] (Table 5).…”

Section: Analysis Of Somatic Mutations In Immunoglobulin Genesmentioning

confidence: 99%

Theoretical analysis of mutation hotspots and their DNA sequence context specificity

Rogozin

Pavlov

2003

Mutation Research/Reviews in Mutation Research

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164

132

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Mutation frequencies vary significantly along nucleotide sequences such that mutations often concentrate at certain positions called hotspots. Mutation hotspots in DNA reflect intrinsic properties of the mutation process, such as sequence specificity, that manifests itself at the level of interaction between mutagens, DNA, and the action of the repair and replication machineries. The hotspots might also reflect structural and functional features of the respective DNA sequences. When mutations in a gene are identified using a particular experimental system, resulting hotspots could reflect the properties of the gene product and the mutant selection scheme. Analysis of the nucleotide sequence context of hotspots can provide information on the molecular mechanisms of mutagenesis. However, the determinants of mutation frequency and specificity are complex, and there are many analytical methods for their study. Here we review computational approaches for analyzing mutation spectra (distribution of mutations along the target genes) that include many mutable (detectable) positions. The following methods are reviewed: derivation of a consensus sequence, application of regression approaches to correlate nucleotide sequence features with mutation frequency, mutation hotspot prediction, analysis of oligonucleotide composition of regions containing mutations, pairwise comparison of mutation spectra, analysis of multiple spectra, and analysis of "context-free" characteristics. The advantages and pitfalls of these methods are discussed and illustrated by examples from the literature. The most reliable analyses were obtained when several methods were combined and information from theoretical analysis and experimental observations was considered simultaneously. Simple, robust approaches should be used with small samples of mutations, whereas combinations of simple and complex approaches may be required for large samples. We discuss several well-documented studies where analysis of mutation spectra has substantially contributed to the current understanding of molecular mechanisms of mutagenesis. The nucleotide sequence context of mutational hotspots is a fingerprint of interactions between DNA and DNA repair, replication, and modification enzymes, and the analysis of hotspot context provides evidence of such interactions. Published by Elsevier B.V.

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Response 1 to 'Smaller role for pol η?'

Cited by 11 publications

References 8 publications

Expression of human AID in yeast induces mutations in context similar to the context of somatic hypermutation at G-C pairs in immunoglobulin genes

Expression of human AID in yeast induces mutations in context similar to the context of somatic hypermutation at G-C pairs in immunoglobulin genes

Correlation of somatic hypermutation specificity and A-T base pair substitution errors by DNA polymerase η during copying of a mouse immunoglobulin κ light chain transgene

Theoretical analysis of mutation hotspots and their DNA sequence context specificity

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