scholarly journals Contribution of DNA polymerase η to immunoglobulin gene hypermutation in the mouse

2005 ◽  
Vol 201 (8) ◽  
pp. 1191-1196 ◽  
Author(s):  
Frédéric Delbos ◽  
Annie De Smet ◽  
Ahmad Faili ◽  
Said Aoufouchi ◽  
Jean-Claude Weill ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Xeroderma Pigmentosum ◽  
Stop Codon ◽  
Immunoglobulin Gene ◽  
Immunoglobulin Genes ◽  
Mutation Profile ◽  
Mutation Pattern ◽  
Deficient Mice ◽  
Dna Polymerase Ι ◽  
Codon Mutation

The mutation pattern of immunoglobulin genes was studied in mice deficient for DNA polymerase η, a translesional polymerase whose inactivation is responsible for the xeroderma pigmentosum variant (XP-V) syndrome in humans. Mutations show an 85% G/C biased pattern, similar to that reported for XP-V patients. Breeding these mice with animals harboring the stop codon mutation of the 129/Olain background in their DNA polymerase ι gene did not alter this pattern further. Although this G/C biased mutation profile resembles that of mice deficient in the MSH2 or MSH6 components of the mismatch repair complex, the residual A/T mutagenesis of polη-deficient mice differs markedly. This suggests that, in the absence of polη, the MSH2–MSH6 complex is able to recruit another DNA polymerase that is more accurate at copying A/T bases, possibly polκ, to assume its function in hypermutation.

scholarly journals DNA polymerase η is the sole contributor of A/T modifications during immunoglobulin gene hypermutation in the mouse

2006 ◽  
Vol 204 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Frédéric Delbos ◽  
Said Aoufouchi ◽  
Ahmad Faili ◽  
Jean-Claude Weill ◽  
Claude-Agnès Reynaud
Keyword(s):  
Dna Repair ◽  
Dna Binding ◽  
Mismatch Repair ◽  
Dna Polymerase ◽  
Immunoglobulin Gene ◽  
Immunoglobulin Genes ◽  
Repair Pathway ◽  
Deficient Mice

Mutations at A/T bases within immunoglobulin genes have been shown to be generated by a repair pathway involving the DNA-binding moiety of the mismatch repair complex constituted by the MSH2–MSH6 proteins, together with DNA polymerase η (pol η). However, residual A/T mutagenesis is still observed upon inactivation in the mouse of each of these factors, suggesting that the panel of activities involved might be more complex. We reported previously (Delbos, F., A. De Smet, A. Faili, S. Aoufouchi, J.-C. Weill, and C.-A. Reynaud. 2005. J. Exp. Med. 201:1191–1196) that residual A/T mutagenesis in pol η–deficient mice was likely contributed by another enzyme not normally involved in hypermutation, DNA polymerase κ, which is mobilized in the absence of the normal polymerase partner. We report the complete absence of A/T mutations in MSH2–pol η double-deficient mice, thus indicating that the residual A/T mutagenesis in MSH2-deficient mice is contributed by pol η, now recruited by uracil N-glycosylase, the second DNA repair pathway involved in hypermutation. We propose that this particular recruitment of pol η corresponds to a profound modification of the function of uracil glycosylase in the absence of the mismatch repair complex, suggesting that MSH2–MSH6 actively prevent uracil glycosylase from error-free repair during hypermutation. pol η thus appears to be the sole contributor of A/T mutations in the normal physiological context.

scholarly journals UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

2006 ◽  
Vol 26 (20) ◽  
pp. 7696-7706 ◽  
Author(s):  
Tsuyoshi Ohkumo ◽  
Yuji Kondo ◽  
Masayuki Yokoi ◽  
Tetsuya Tsukamoto ◽  
Ayumi Yamada ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Somatic Hypermutation ◽  
Uv Light ◽  
Tumor Formation ◽  
Skin Tumor ◽  
Mesenchymal Tumors ◽  
Uv Sensitivity ◽  
Tumor Susceptibility ◽  
Deficient Mice ◽  
Dna Polymerase Ι

ABSTRACT DNA polymerase η (Pol η) is the product of the Polh gene, which is responsible for the group variant of xeroderma pigmentosum, a rare inherited recessive disease which is characterized by susceptibility to sunlight-induced skin cancer. We recently reported in a study of Polh mutant mice that Pol η is involved in the somatic hypermutation of immunoglobulin genes, but the cancer predisposition of Polh −/− mice has not been examined until very recently. Another translesion synthesis polymerase, Pol ι, a Pol η paralog encoded by the Poli gene, is naturally deficient in the 129 mouse strain, and the function of Pol ι is enigmatic. Here, we generated Polh Poli double-deficient mice and compared the tumor susceptibility of them with Polh- or Poli-deficient animals under the same genetic background. While Pol ι deficiency does not influence the UV sensitivity of mouse fibroblasts irrespective of Polh genotype, Polh Poli double-deficient mice show slightly earlier onset of skin tumor formation. Intriguingly, histological diagnosis after chronic treatment with UV light reveals that Pol ι deficiency leads to the formation of mesenchymal tumors, such as sarcomas, that are not observed in Polh −/− mice. These results suggest the involvement of the Pol η and Pol ι proteins in UV-induced skin carcinogenesis.

Funktionelle Relevanz der Stop-Codon Mutation rs61757459 in Vaspin (SerpinA12)

2013 ◽  
Vol 8 (S 01) ◽  
Author(s):  
J Breitfeld ◽  
JT Heiker ◽  
Y Böttcher ◽  
D Schleinitz ◽  
A Tönjes ◽  
...  
Keyword(s):  
Stop Codon ◽  
Stop Codon Mutation ◽  
Codon Mutation

scholarly journals Human DNA Polymerase ι Incorporates dCTP Opposite Template G via a G.C+ Hoogsteen Base Pair

Structure ◽  
2005 ◽  
Vol 13 (10) ◽  
pp. 1569-1577 ◽  
Author(s):  
Deepak T. Nair ◽  
Robert E. Johnson ◽  
Louise Prakash ◽  
Satya Prakash ◽  
Aneel K. Aggarwal
Keyword(s):  
Dna Polymerase ◽  
Base Pair ◽  
Human Dna ◽  
Dna Polymerase Ι

Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus

1993 ◽  
Vol 5 (6) ◽  
pp. 647-656 ◽  
Author(s):  
Jianzhu Chen ◽  
Mary Trounstine ◽  
Frederick W. Alt ◽  
Faith Young ◽  
Carole Kurahara ◽  
...  
Keyword(s):  
B Cell ◽  
Gene Rearrangement ◽  
Immunoglobulin Gene ◽  
Targeted Deletion ◽  
Immunoglobulin Gene Rearrangement ◽  
Deficient Mice

A novel stop codon mutation in the PMP22 gene associated with a variable phenotype

2004 ◽  
Vol 14 (5) ◽  
pp. 313-320 ◽  
Author(s):  
K.T Abe ◽  
A.M.M Lino ◽  
M.T.A Hirata ◽  
R.C.M Pavanello ◽  
M.W.I Brotto ◽  
...  
Keyword(s):  
Stop Codon ◽  
Pmp22 Gene ◽  
Stop Codon Mutation ◽  
Variable Phenotype ◽  
Codon Mutation

Response of human DNA polymerase ι promoter to N-methyl-N′-nitro-N-nitrosoguanidine

2010 ◽  
Vol 29 (1) ◽  
pp. 79-86 ◽  
Author(s):  
Huifang Zhu ◽  
Yanfeng Fan ◽  
Hongjuan Jiang ◽  
Jing Shen ◽  
Hongyan Qi ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Human Dna ◽  
Dna Polymerase Ι
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