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首页> 外文期刊>Journal of cellular biochemistry. >The mismatch repair-mediated cell cycle checkpoint response to fluorodeoxyuridine.
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The mismatch repair-mediated cell cycle checkpoint response to fluorodeoxyuridine.

机译：错配修复介导的细胞周期检查点对氟脱氧尿苷的反应。

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摘要

The loss of DNA mismatch repair (MMR) is responsible for hereditary nonpolyposis colorectal cancer and a subset of sporadic tumors. Acquired resistance or tolerance to some anti-cancer drugs occurs when MMR function is impaired. 5-Fluorouracil (FU), an anti-cancer drug used in the treatment of advanced colorectal and other cancers, and its metabolites are incorporated into RNA and DNA and inhibit thymidylate synthase resulting in depletion of dTTP and incorporation in DNA of uracil. Although the MMR deficiency has been implicated in tolerance to FU, the mechanism of cell killing remains unclear. Here, we examine the cellular response to fluorodeoxyuridine (FdU) and the role of the MMR system. After brief exposure of cells to low doses of FdU, MMR mediates DNA damage signaling during S-phase and triggers arrest in G2/M in the first cell cycle in a manner requiring MutSalpha, MutLalpha, and DNA replication. Cell cycle arrest is mediated by ATR kinase and results in phosphorylation of Chk1 and SMC1. MutSalpha binds FdU:G mispairs in vitro consistent with its being a DNA damage sensor. Prolonged treatment with FdU results in an irreversible arrest in G2 that is independent of MMR status and leads to the accumulation of DNA lesions that are targeted by the base excision repair (BER) pathway. Thus, MMR can act as a direct sensor of FdU-mediated DNA lesions eliciting cell cycle arrest via the ATR/Chk1 pathway. However, at higher levels of damage, other damage surveillance pathways such as BER also play important roles.
机译：DNA错配修复（MMR）的丢失是遗传性非息肉病性结直肠癌和一部分散发性肿瘤的原因。 MMR功能受损时，会出现对某些抗癌药的获得性耐药性或耐受性。 5-氟尿嘧啶（FU）是一种用于治疗晚期结直肠癌和其他癌症的抗癌药物，其代谢物被掺入RNA和DNA中并抑制胸苷酸合酶，导致dTTP耗竭并掺入尿嘧啶DNA中。尽管MMR缺乏与FU耐受性有关，但细胞杀伤机制仍不清楚。在这里，我们检查了细胞对氟脱氧尿苷（FdU）的反应以及MMR系统的作用。在将细胞短暂暴露于低剂量的FdU之后，MMR在S期介导DNA损伤信号传导，并在第一个细胞周期中以要求MutSalpha，MutLalpha和DNA复制的方式触发G2 / M停滞。细胞周期停滞是由ATR激酶介导的，并导致Chk1和SMC1磷酸化。 MutSalpha在体外与FdU：G错误配对结合，这与其是DNA损伤传感器一致。长时间使用FdU进行治疗会导致G2中不可逆的停滞，这与MMR状态无关，并导致碱基切除修复（BER）途径靶向的DNA损伤的积累。因此，MMR可以作为FdU介导的DNA损伤的直接传感器，通过ATR / Chk1途径引起细胞周期停滞。但是，在较高的损坏水平下，其他损坏监视路径（例如BER）也起着重要作用。

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