Mutagenesis by transient misalignment.

Kunkel, Thomas A.; Soni, Anjali

doi:10.1016/s0021-9258(18)68106-2

Cited by 260 publications

(60 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…mation of DNA adducts by 4AB in Salmonella predominantly at the C(8) position of guanine (KAD-LUBAR et al. 1982), (2) the finding that such adducts cause the guanines in the majority of 4AB-adducted poly (CpG) molecules (a sequence motif found at the complex frameshift hotspot) to reside in the s p conformation (BROYDE et al 1985;SHAPIRO et al 1986), (3) the possibility for the 06 and N-7 atoms of modified guanines in the syn conformation to mispair with the N-1 and fl of guanine or with the N6 and N-1 of adenine, resulting in transversions (DRAKE and BALTZ 1976;TOPAL and FRESCO 1976), (4) the observation that in the pres ence of pKM101, -80% of the 4 B i n d u c e d base substitutions are transversions (Figure 2), and (5) the well documented ability of DNA polymerases (when copying undamaged templates in vitro) to produce frameshift errors that are mediated by a nucleotide misinsertion and a subsequent slippage event (KUNKEL and SONI 1988;BEBENEK and KUNKEL 1990;KUNKEL 1990;BEBENEK et al 1992).…”

Section: 'mentioning

confidence: 99%

Complex frameshift mutations mediated by plasmid pKM101: mutational mechanisms deduced from 4-aminobiphenyl-induced mutation spectra in Salmonella.

1994

View full text Add to dashboard Cite

We used colony probe hybridization and polymerase chain reaction/DNA sequence analysis to determine the mutations in approximately 2,400 4-aminobiphenyl (4-AB) +S9-induced revertants of the -1 frameshift allele hisD3052 and of the base-substitution allele hisG46 of Salmonella typhimurium. Most of the mutations occurred at sites containing guanine, which is the primary base at which 4-AB forms DNA adducts. A hotspot mutation involving the deletion of a CG or GC within the sequence CGCGCGCG accounted for 100 and 99.9%, respectively, of the reversion events at the hisD3052 allele in the pKM101 plasmid-minus strains TA1978 (uvr+) and TA1538 (delta uvrB). In strain TA98 (delta uvrB, pKM101), which contained the SOS DNA repair system provided by the pKM101 plasmid, approximately 85% of the revertants also contained the hotspot deletion; the remaining approximately 15% contained one of two types of mutations: (1) complex frameshifts that can be described as a -2 or +1 frameshift and an associated base substitution and (2) deletions of the CC or GG sequences that flank the hotspot site (CCGCGCGCGG). We propose a misincorporation/slippage model to account for these mutations in which (1) pKM101-mediated misincorporation and translesion synthesis occurs across a 4-AB-adducted guanine; (2) the instability of such a mispairing and/or the presence of the adduct leads to strand slippage in a run of repeated bases adjacent to the adducted guanine; and (3) continued DNA synthesis from the slipped intermediate produces a frameshift associated with a base substitution. This model readily accounts for the deletion of the CC or GG sequences flanking the hotspot site, indicating that these mutations are, in fact, complex mutations in disguise (i.e., cryptic complex frameshifts). The inferred base-substitution specificity associated with the complex frameshifts at the hisD3052 allele (primarily G.C-->T.A transversions) is consistent with the finding that 4-AB induced primarily G.C-->T.A transversions at the hisG46 base-substitution allele. The model also provides a framework for understanding the different relative mutagenic potencies of 4-AB at the two alleles in the various DNA repair backgrounds of Salmonella.

show abstract

Section: 'mentioning

confidence: 99%

Complex frameshift mutations mediated by plasmid pKM101: mutational mechanisms deduced from 4-aminobiphenyl-induced mutation spectra in Salmonella.

1994

View full text Add to dashboard Cite

show abstract

“…These substitutions for the vast majority converted the base flanking the repeat, to the base constituting the repeat (Figure 2G). They are thus probably the result of polymerase slippage events, following a mechanism akin to the previously described bacterial dislocation mutagenesis (Kunkel and Soni, 1988). Thirdly, G:C>A:T transitions in CpG sites strongly depend on CpG content, but are inversely correlated with the fraction of CpG islands (Figure 2E).…”

Section: Somatic Substitutions In Mmr-deficient Hypermutatorsmentioning

confidence: 52%

Decision letter: Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks

2014

View full text Add to dashboard Cite

DNA replication errors that persist as mismatch mutations make up the molecular fingerprint of mismatch repair (MMR)-deficient tumors and convey them with resistance to standard therapy. Using whole-genome and whole-exome sequencing, we here confirm an MMR-deficient mutation signature that is distinct from other tumor genomes, but surprisingly similar to germ-line DNA, indicating that a substantial fraction of human genetic variation arises through mutations escaping MMR. Moreover, we identify a large set of recurrent indels that may serve to detect microsatellite instability (MSI). Indeed, using endometrial tumors with immunohistochemically proven MMR deficiency, we optimize a novel marker set capable of detecting MSI and show it to have greater specificity and selectivity than standard MSI tests. Additionally, we show that recurrent indels are enriched for the 'DNA double-strand break repair by homologous recombination' pathway. Consequently, DSB repair is reduced in MMR-deficient tumors, triggering a dosedependent sensitivity of MMR-deficient tumor cultures to DSB inducers.

show abstract

“…The proportion of G C C and G C G changes increased with altered dNTPs, most dramatically in rnr1Y285F and rnr1Y285A samples (note change in y-axis), which were highly correlated ( r s = 0.7284). The G C C and G C G sequence contexts are mutated in rnr1Y285A , as detected by whole genome sequencing (9) possibly as a result of increased extension after misincorporation of dTTP, which is in excess, superseding proofreading (51).…”

Section: Resultsmentioning

confidence: 99%

Complex Mutation Profiles in Mismatch Repair and Ribonucleotide Reductase Mutants Reveal Novel Repair Substrate Specificity of MutS Homolog (MSH) Complexes

Bard

Loll-Krippleber

et al. 2021

Preprint

View full text Add to dashboard Cite

Determining mutation signatures is standard for understanding the etiology of human tumors and informing cancer treatment. Multiple determinants of DNA replication fidelity prevent mutagenesis that leads to carcinogenesis, including regulation of free deoxyribonucleoside triphosphate (dNTP) pools and the repair of base mismatches. We utilized a targeted deep-sequencing approach to determine mutational signatures associated with mismatch repair (MMR) pathway defects. By combining rnr1 and msh mutations to increase dNTP levels and alter the mutational load, we observed previously unreported specificities of Msh2-Msh3 and Msh2-Msh6. Msh2-Msh3 is uniquely able to direct repair of G/C single base deletions in GC runs, while Msh2-Msh6 specifically directs repair of substitutions at G/C dinucleotides. We also identified broader sequence contexts that influence variant profiles in different genetic backgrounds and found that there was not necessarily a simple additive relationship of mutation profiles in double mutants. Our results have implications for interpreting mutation signatures from human tumors, particularly when MMR is defective.

show abstract

Mutagenesis by transient misalignment.

Cited by 260 publications

References 38 publications

Complex frameshift mutations mediated by plasmid pKM101: mutational mechanisms deduced from 4-aminobiphenyl-induced mutation spectra in Salmonella.

Complex frameshift mutations mediated by plasmid pKM101: mutational mechanisms deduced from 4-aminobiphenyl-induced mutation spectra in Salmonella.

Decision letter: Mismatch repair deficiency endows tumors with a unique mutation signature and sensitivity to DNA double-strand breaks

Complex Mutation Profiles in Mismatch Repair and Ribonucleotide Reductase Mutants Reveal Novel Repair Substrate Specificity of MutS Homolog (MSH) Complexes

Contact Info

Product

Resources

About