DNA polymerases η and θ function in the same genetic pathway to generate mutations at A/T during somatic hypermutation of Ig genes

Keiji Masuda, Rika Ouchida, Masaki Hikida, Tomohiro Kurosaki, Masayuki Yokoi, Chikahide Masutani, Mineaki Seki, Richard D. Wood, Fumio Hanaoka, Jiyang O-Wang

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Abstract

Somatic hypermutation of the Ig genes requires the activity of multiple DNA polymerases to ultimately introduce mutations at both A/T and C/G base pairs. Mice deficient for DNA polymerase η(POLH) exhibited an ∼80% reduction of the mutations at A/T, whereas absence of polymerase θ (POLQ) resulted in ∼20% reduction of both A/T and C/G mutations. To investigate whether the residual A/T mutations observed in the absence of POLH are generated by POLQ and how these two polymerases might cooperate or compete with each other to generate A/T mutations, here we have established mice deficient for both POLH and POLQ. Polq-/- Polh-/- mice, however, did not show a further decrease of A/T mutations as compared with Polh-/- mice, suggesting that POLH and POLQ function in the same genetic pathway in the generation of these mutations. Frequent misincorporation of nucleotides, in particular opposite template T, is a known feature of POLH, but the efficiency of extension beyond the misincorporation differs significantly depending on the nature of the mispairing. Remarkably, we found that POLQ catalyzed extension more efficiently than POLH from all types of mispaired termini opposite A or T. Moreover, POLQ was able to extend mispaired termini generated by POLH albeit at a relatively low efficiency. These results reveal genetic and biochemical interactions between POLH and POLQ and suggest that POLQ might cooperate with POLH to generate some of the A/T mutations during the somatic hypermutation of Ig genes.

Original languageEnglish
Pages (from-to)17387-17394
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number24
DOIs
Publication statusPublished - Jun 15 2007

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Immunoglobulin Genes
DNA-Directed DNA Polymerase
Genes
Mutation
Nucleotides
Base Pairing
Molecular Biology

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

DNA polymerases η and θ function in the same genetic pathway to generate mutations at A/T during somatic hypermutation of Ig genes. / Masuda, Keiji; Ouchida, Rika; Hikida, Masaki; Kurosaki, Tomohiro; Yokoi, Masayuki; Masutani, Chikahide; Seki, Mineaki; Wood, Richard D.; Hanaoka, Fumio; O-Wang, Jiyang.

In: Journal of Biological Chemistry, Vol. 282, No. 24, 15.06.2007, p. 17387-17394.

Research output: Contribution to journalArticle

Masuda, K, Ouchida, R, Hikida, M, Kurosaki, T, Yokoi, M, Masutani, C, Seki, M, Wood, RD, Hanaoka, F & O-Wang, J 2007, 'DNA polymerases η and θ function in the same genetic pathway to generate mutations at A/T during somatic hypermutation of Ig genes', Journal of Biological Chemistry, vol. 282, no. 24, pp. 17387-17394. https://doi.org/10.1074/jbc.M611849200
Masuda, Keiji ; Ouchida, Rika ; Hikida, Masaki ; Kurosaki, Tomohiro ; Yokoi, Masayuki ; Masutani, Chikahide ; Seki, Mineaki ; Wood, Richard D. ; Hanaoka, Fumio ; O-Wang, Jiyang. / DNA polymerases η and θ function in the same genetic pathway to generate mutations at A/T during somatic hypermutation of Ig genes. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 24. pp. 17387-17394.
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AU - Masuda, Keiji

AU - Ouchida, Rika

AU - Hikida, Masaki

AU - Kurosaki, Tomohiro

AU - Yokoi, Masayuki

AU - Masutani, Chikahide

AU - Seki, Mineaki

AU - Wood, Richard D.

AU - Hanaoka, Fumio

AU - O-Wang, Jiyang

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N2 - Somatic hypermutation of the Ig genes requires the activity of multiple DNA polymerases to ultimately introduce mutations at both A/T and C/G base pairs. Mice deficient for DNA polymerase η(POLH) exhibited an ∼80% reduction of the mutations at A/T, whereas absence of polymerase θ (POLQ) resulted in ∼20% reduction of both A/T and C/G mutations. To investigate whether the residual A/T mutations observed in the absence of POLH are generated by POLQ and how these two polymerases might cooperate or compete with each other to generate A/T mutations, here we have established mice deficient for both POLH and POLQ. Polq-/- Polh-/- mice, however, did not show a further decrease of A/T mutations as compared with Polh-/- mice, suggesting that POLH and POLQ function in the same genetic pathway in the generation of these mutations. Frequent misincorporation of nucleotides, in particular opposite template T, is a known feature of POLH, but the efficiency of extension beyond the misincorporation differs significantly depending on the nature of the mispairing. Remarkably, we found that POLQ catalyzed extension more efficiently than POLH from all types of mispaired termini opposite A or T. Moreover, POLQ was able to extend mispaired termini generated by POLH albeit at a relatively low efficiency. These results reveal genetic and biochemical interactions between POLH and POLQ and suggest that POLQ might cooperate with POLH to generate some of the A/T mutations during the somatic hypermutation of Ig genes.

AB - Somatic hypermutation of the Ig genes requires the activity of multiple DNA polymerases to ultimately introduce mutations at both A/T and C/G base pairs. Mice deficient for DNA polymerase η(POLH) exhibited an ∼80% reduction of the mutations at A/T, whereas absence of polymerase θ (POLQ) resulted in ∼20% reduction of both A/T and C/G mutations. To investigate whether the residual A/T mutations observed in the absence of POLH are generated by POLQ and how these two polymerases might cooperate or compete with each other to generate A/T mutations, here we have established mice deficient for both POLH and POLQ. Polq-/- Polh-/- mice, however, did not show a further decrease of A/T mutations as compared with Polh-/- mice, suggesting that POLH and POLQ function in the same genetic pathway in the generation of these mutations. Frequent misincorporation of nucleotides, in particular opposite template T, is a known feature of POLH, but the efficiency of extension beyond the misincorporation differs significantly depending on the nature of the mispairing. Remarkably, we found that POLQ catalyzed extension more efficiently than POLH from all types of mispaired termini opposite A or T. Moreover, POLQ was able to extend mispaired termini generated by POLH albeit at a relatively low efficiency. These results reveal genetic and biochemical interactions between POLH and POLQ and suggest that POLQ might cooperate with POLH to generate some of the A/T mutations during the somatic hypermutation of Ig genes.

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