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首页> 外文期刊>Mutation Research: International Journal on Mutagenesis, Chromosome Breakage and Related Subjects >A role for mismatch repair in production of chromosome aberrations by methylating agents in human cells.
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A role for mismatch repair in production of chromosome aberrations by methylating agents in human cells.

机译：失配修复在人类细胞甲基化剂产生染色体畸变中的作用。

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We have shown previously that certain alkylation products, or alkylation derived lesions, which induce chromosome aberrations (abs) persist for at least two cell cycles in Chinese hamster ovary cells. The increase in abs in the second cycle after treatment contrasts with the classical observation of reduction in ab yield with successive mitoses following ionizing radiation. Here we present evidence that processing of lesions by mismatch repair is a mechanism for ab induction by methylating agents. Our previous studies implicated O6-methylguanine (O6MeG) as an important lesion in induction of abs, particularly in the second cell cycle after treatment. In the absence of repair of O6MeG by alkylguanine DNA alkyltransferase (AGT), new abs were induced in the second cycle after treatment with e.g. methylnitronitrosoguanidine (MNNG) and methylnitrosourea (MNU). Thus, we hypothesized that abs were produced not by O6MeG or its repair in the first S phase, but by subsequent processing of the lesions. We suggested that after replication proceeded past the O6MeG lesion in the first S phase, inserting an incorrect base on the newly synthesized strand, recognition and repair by mismatch repair in the second S phase led to a chromosome ab. Here we used MT1 cells, a human lymphoblastoid cell line that has a defect in strand-specific mismatch repair. MT1 cells are alkylation tolerant and have a mutator phenotype, compared with their parent line, TK6; both MT1 and TK6 cells lack AGT so do not remove the methyl group from O6MeG. While the initial levels of abs at the first metaphase were similar in MT1 and TK6 cells, ab levels in MT1 cells were greatly reduced in the second and third cell cycles following treatment with MNNG, dimethylnitrosamine and MNU, in contrast with the parent TK6 cells, which had more abs in the second cell cycle than in the first. This supports the hypothesis that repair of mismatched base pairs involving O6MeG is one mechanism for induction of chromosome abs. In contrast to the difference in response to methylating agents between TK6 cells and mismatch repair-deficient MT1 cells, the profile of ab induction by an ethylating agent, ethylnitronitrosourea, was similar in MT1 cells to those for TK6 cells and CHO cells.
机译：先前我们已经表明，某些引起染色体畸变（abs）的烷基化产物或烷基化衍生的病变在中国仓鼠卵巢细胞中持续至少两个细胞周期。在治疗后第二个周期中，abs的增加与电离辐射后连续有丝分裂的ab产量降低的经典观察结果相反。在这里，我们提供证据表明，通过错配修复对损伤进行处理是甲基化试剂引起ab诱导的机制。我们以前的研究暗示O6-甲基鸟嘌呤（O6MeG）是诱导abs的重要病变，特别是在治疗后的第二个细胞周期中。在没有通过烷基鸟嘌呤DNA烷基转移酶（AGT）修复O 6 MeG的情况下，在用例如α-氨基丁酸处理的第二周期中诱导出新的abs。甲基亚硝基硝基胍（MNNG）和甲基亚硝基脲（MNU）。因此，我们假设Abs不是由O6MeG或其在第一个S期的修复产生的，而是由随后的病变处理产生的。我们建议，在第一个S期复制过程超过O6MeG病变后，在新合成的链上插入一个不正确的碱基，在第二个S期中通过错配修复进行识别和修复导致染色体ab。在这里，我们使用了MT1细胞，这是一种人类淋巴母细胞系，在链特异性错配修复中存在缺陷。与母系TK6相比，MT1细胞具有烷基化耐受性，并具有突变表型。 MT1和TK6细胞均缺乏AGT，因此请勿从O6MeG中除去甲基。尽管第一中期的abs初始水平在MT1和TK6细胞中相似，但与亲本TK6细胞相比，在用MNNG，二甲基亚硝胺和MNU处理后的第二和第三细胞周期中，MT1细胞中的ab水平大大降低了，与第二个细胞周期相比，第二个细胞周期的绝对吸收更多。这支持以下假设：涉及O6MeG的错配碱基对的修复是诱导染色体abs的一种机制。与TK6细胞和错配修复缺陷型MT1细胞之间对甲基化试剂的响应差异不同，在MT1细胞中，乙基化试剂乙基亚硝基亚硝基脲的ab诱导概况与TK6细胞和CHO细胞相似。

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