Interplay of DNA repair pathways controls methylation damage toxicity in Saccharomyces cerevisiae

被引:12
|
作者
Cejka, Petr [1 ]
Jiricny, Josef [1 ,2 ]
机构
[1] Univ Zurich, Inst Mol Canc Res, CH-8057 Zurich, Switzerland
[2] ETH, Swiss Fed Inst Technol, Dept Biol, CH-8093 Zurich, Switzerland
基金
美国国家科学基金会;
关键词
D O I
10.1534/genetics.108.089979
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:1835 / 1844
页数:10
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