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

被引:101
作者
Martomo, SA
Yang, WW
Wersto, RP
Ohkumo, T
Kondo, Y
Yokoi, M
Masutani, C
Hanaoka, F
Gearhart, PJ
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
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.
引用
收藏
页码:8656 / 8661
页数:6
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