Interplay of DNA repair pathways controls methylation damage toxicity in Saccharomyces cerevisiae
Interplay of DNA repair pathways controls methylation damage toxicity in Saccharomyces cerevisiae
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DOI：
10.1534/genetics.108.089979
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发表时间：
2008-08-01
期刊：
影响因子：
3.3
通讯作者：
Jiricny, Josef
中科院分区：
文献类型：
--
作者：
Cejka, Petr;Jiricny, Josef
SNI类甲基化试剂广泛应用于癌症化疗，但对其作用机制知之甚少。特别是，主要的细胞毒性损伤O-6-甲基鸟嘌呤((Me)G)是如何导致细胞死亡的尚不清楚。一种假说认为，在DNA复制过程中，错配修复蛋白与(Me)G/T错对的结合会触发细胞周期停滞和细胞死亡。另一种假说认为。(Me)G细胞毒性与MMR系统对(Me)G碱基对的无效处理有关。在这项研究中，我们提供了令人信服的遗传学证据来支持后一种假设。用典型的SNI型甲基化试剂N-甲基-N‘-亚硝基胍(MNNG)处理4644个缺失突变的酿酒酵母，发现MMR是使细胞对MNNG敏感的唯一途径。相比之下，同源重组(HR)、复制后修复、DNA解旋酶、中染色质维持因子具有保护作用。酵母菌细胞对抗。这种化学物质的细胞毒性。值得注意的是，DNA损伤信号蛋白在MNNG反应中起到保护而不是敏化的作用。综上所述，这一证据表明，酵母中的(Me)含G损伤必须经过处理才能具有细胞毒性。
Methylating agents of SNI type are widely used in cancer chemotherapy but, their mode of action is poorly understood. In particular, it is unclear how the primary cytotoxic lesion, O-6-methylguanine ((Me)G), causes cell death. One hypothesis stipulates that binding of mismatch repair (NMR) proteins to (Me)G/T mispairs arising during DNA replication triggers cell-cycle arrest and cell death. An alternative hypothesis posits that. (Me)G cytotoxicity is linked to futile processing of (Me)G-containing base pairs by die MMR system. In this study, we provide compelling genetic evidence in support, of the latter hypothesis. Treatment of 4644 deletion mutants of Saccharomyes cerevisiae with the prototypic SNI-type methylating agent N-methyl-N'-nitrosoguanidine (MNNG) identified MMR is the only pathway that sensitizes cells to MNNG. In contrast, homologous recombination (HR), postreplicative repair, DNA helicases, mid chromatin maintenace factors protect. yeast cells against. the cytotoxicity of this chemical. Notably, DNA damage signaling proteins played a protective rather than sensitizing role ill the MNNG response. Taken together, this evidence demonstrates that (Me)G-containing lesions in yeast must be processed to be cytotoxic.