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Different mutation signatures in DNA polymerase η- and MSH6-deficient mice suggest separate roles in antibody diversification
被引:101
作者:

Martomo, SA
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机构: NIA, Lab Mol Gerontol, NIH, Res Resources Branch, Baltimore, MD 21224 USA

Yang, WW
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机构: NIA, Lab Mol Gerontol, NIH, Res Resources Branch, Baltimore, MD 21224 USA

Wersto, RP
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机构: NIA, Lab Mol Gerontol, NIH, Res Resources Branch, Baltimore, MD 21224 USA

Ohkumo, T
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机构: NIA, Lab Mol Gerontol, NIH, Res Resources Branch, Baltimore, MD 21224 USA

Kondo, Y
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机构: NIA, Lab Mol Gerontol, NIH, Res Resources Branch, Baltimore, MD 21224 USA

Yokoi, M
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机构: NIA, Lab Mol Gerontol, NIH, Res Resources Branch, Baltimore, MD 21224 USA

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Hanaoka, F
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h-index: 0
机构: NIA, Lab Mol Gerontol, NIH, Res Resources Branch, Baltimore, MD 21224 USA

Gearhart, PJ
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机构: NIA, Lab Mol Gerontol, NIH, Res Resources Branch, Baltimore, MD 21224 USA
机构:
[1] NIA, Lab Mol Gerontol, NIH, Res Resources Branch, Baltimore, MD 21224 USA
[2] Osaka Univ, Grad Sch Frontier Biosci, Osaka 5650871, Japan
[3] RIKEN, Discovery Res Inst, Wako, Saitama 3510198, Japan
[4] Japan Sci & Technol Agcy, Solut Oriented Res Sci & Technol, Wako, Saitama 3510198, Japan
来源:
关键词:
class switch recombination;
somatic hypermutation;
low-fidelity DNA polymerase;
mismatch repair;
D O I:
10.1073/pnas.0501852102
中图分类号:
O [数理科学和化学];
P [天文学、地球科学];
Q [生物科学];
N [自然科学总论];
学科分类号:
07 ;
0710 ;
09 ;
摘要:
Hypermutation in immunoglobulin genes produces a high frequency of substitutions of all four bases, which are likely generated by low-fidelity DNA polymerases. Indeed, humans deficient for DNA polymerase (pol) eta have decreased substitutions of A-T base pairs in variable and switch regions. To study the role of pol eta in a genetically tractable system, we created mice lacking pol eta. B cells from Polh(-/-) mice produced normal amounts of IgG, indicating that pol eta does not affect class switch recombination. Similar to their human counterparts, variable and switch regions from Polh(-/-) mice had fewer substitutions of A-T base pairs and correspondingly more mutations of C-G base pairs, which firmly establishes a central role for pol eta in hypermutation. Notably, the location and types of substitutions differ markedly from those in Msh6(-/-) clones, which also have fewer A-T mutations. The data suggest that pol eta preferentially synthesizes a repair patch on the nontranscribed strand, whereas MSH6 functions to generate the patch.
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页码:8656 / 8661
页数:6
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