ArticleProceedings of the National Academy of Sciences of the United States of America2013
Mechanism of somatic hypermutation at the WA motif by human DNA polymerase η.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed.
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- Review
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- In crystallo observation of active site dynamics and transient metal ion binding within DNA polymerases.Structural dynamics (Melville, N.Y.) · 2023Article
- RNA-guided DNA base damage repair via DNA polymerase-mediated nick translation.Nucleic acids research · 2023Article
- Structures of LIG1 that engage with mutagenic mismatches inserted by polβ in base excision repair.Nature communications · 2022Article
- Structural and Molecular Kinetic Features of Activities of DNA Polymerases.International journal of molecular sciences · 2022Review
- Differential ETS1 binding to T:G mismatches within a CpG dinucleotide contributes to C-to-T somatic mutation rate of the IDH2 hotspot at codon Arg140.DNA repair · 2022Article
- In crystallo observation of three metal ion promoted DNA polymerase misincorporation.Nature communications · 2022Article
- Incorporation of 5',8-cyclo-2'deoxyadenosines by DNA repair polymerases via base excision repair.DNA repair · 2022Article
- Gastric DLBCL clonal evolution as function of patient age.Frontiers in immunology · 2022Article
- Human MettL3-MettL14 RNA adenine methyltransferase complex is active on double-stranded DNA containing lesions.Nucleic acids research · 2021Article
- Immune pathways and TP53 missense mutations are associated with longer survival in canine osteosarcoma.Communications biology · 2021Article
- Mechanism of genome instability mediated by human DNA polymerase mu misincorporation.Nature communications · 2021Article
- Multiple deprotonation paths of the nucleophile 3'-OH in the DNA synthesis reaction.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Preferential CEBP binding to T:G mismatches and increased C-to-T human somatic mutations.Nucleic acids research · 2021Article
- Learning the heterogeneous hypermutation landscape of immunoglobulins from high-throughput repertoire data.Nucleic acids research · 2020Article
- Environmental Effects on Guanine-Thymine Mispair Tautomerization Explored with Quantum Mechanical/Molecular Mechanical Free Energy Simulations.Journal of the American Chemical Society · 2020Article
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6 authors.
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Abstract
Somatic hypermutation is programmed base substitutions in the variable regions of Ig genes for high-affinity antibody generation. Two motifs, RGYW and WA (R, purine; Y, pyrimidine; W, A or T), have been found to be somatic hypermutation hotspots. Overwhelming evidence suggests that DNA polymerase η (Pol η) is responsible for converting the WA motif to WG by misincorporating dGTP opposite the templating T. To elucidate the molecular mechanism, crystal structures and kinetics of human Pol η substituting dGTP for dATP in four sequence contexts, TA, AA, GA, and CA, have been determined and compared. The T:dGTP wobble base pair is stabilized by Gln-38 and Arg-61, two uniquely conserved residues among Pol η. Weak base paring of the W (T:A or A:T) at the primer end and their distinct interactions with Pol η lead to misincorporation of G in the WA motif. Between two WA motifs, our kinetic and structural data indicate that A-to-G mutation occurs more readily in the TA context than AA. Finally, Pol η can extend the T:G mispair efficiently to complete the mutagenesis.
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