DNA polymerase η contributes to strand bias of mutations of A versus T in immunoglobulin genes
DNA polymerase η contributes to strand bias of mutations of A versus T in immunoglobulin genes
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DOI：
10.4049/jimmunol.174.12.7781
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发表时间：
2005-06-15
影响因子：
4.4
通讯作者：
Gearhart, PJ
中科院分区：
文献类型：
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作者：
Mayorov, VI;Rogozin, IB;Gearhart, PJ
DNA聚合酶（pol）eta参与IG基因中A：T碱基的超突变，因为缺乏该聚合酶的人对这些碱基的置换较少。为了确定聚合酶eta是否也是众所周知的非转录链上A与T突变偏好的原因，我们对三名缺乏聚合酶eta的着色性干皮病变异（XP-V）患者的可变区进行了测序。重排的J（H）4基因片段下游内含子区的突变频率在XP-V和对照克隆之间是相似的;然而，在XP-V克隆中有较少的A：T碱基突变和相应更多的C：G碱基取代（p < 10（-7））。与对照克隆相比，XP-V克隆中A核苷酸突变与T核苷酸突变的偏倚显著更小，而两组中C和G核苷酸突变的频率相同。在WA序列基序的突变分析表明，聚合酶eta产生更多的突变A比T的非转录链。来自聚合酶eta缺陷型B细胞的体内数据与酶的体外特异性良好相关。因为聚合酶eta插入更多的突变相对于模板T比模板A，它会产生更多的替代A上新合成的链。
DNA polymerase (pol) eta participates in hypermutation of A:T bases in Ig genes because humans deficient for the polymerase have fewer substitutions of these bases. To determine whether polymerase eta is also responsible for the well-known preference for mutations of A vs T on the nontranscribed strand, we sequenced variable regions from three patients with xeroderma pigmentosum variant (XP-V) disease, who lack polymerase eta. The frequency of mutations in the intronic region downstream of rearranged J(H)4 gene segments was similar between XP-V and control clones; however, there were fewer mutations of A:T bases and correspondingly more substitutions of C:G bases in the XP-V clones (p < 10(-7)). There was significantly less of a bias for mutations of A compared with T nucleotides in the XP-V clones compared with control clones, whereas the frequencies for mutations of C and G were identical in both groups. An analysis of mutations in the WA sequence motif suggests that polymerase eta generates more mutations of A than T on the nontranscribed strand. This in vivo data from polymerase eta-deficient B cells correlates well with the in vitro specificity of the enzyme. Because polymerase eta inserts more mutations opposite template T than template A, it would generate more substitutions of A on the newly synthesized strand.