MLH1‐mediated recruitment of FAN1 to chromatin for the induction of apoptosis triggered by O6‐methylguanine
MLH1‐mediated recruitment of FAN1 to chromatin for the induction of apoptosis triggered by O6‐methylguanine
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MLH1介导的FAN1募集至染色质以诱导O6-甲基鸟嘌呤引发的细胞凋亡
DOI：
10.1111/gtc.12748
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发表时间：
2020
期刊：
影响因子：
2.1
通讯作者：
Hidaka Masumi
中科院分区：
文献类型：
--
作者：
Rikitake Mihoko;Fujikane Ryosuke;Obayashi Yuko;Oka Kyoko;Ozaki Masao;Hidaka Masumi
O6-甲基鸟嘌呤(O6-Meg)是DNA中烷基化产物，具有诱变性和细胞毒性，并以错配修复(MMR)蛋白依赖的方式诱导细胞凋亡。为了了解O6-Meg诱导细胞凋亡的分子机制，我们对FANCD2和FANCI相关核酸酶1(FAN1)进行了功能分析，FAN1被确定为MLH1的相互作用伙伴。免疫沉淀分析表明，经N-甲基-N-亚硝脲(MNU)处理后，FAN1与MLH1和MSH2相互作用，表明FAN1-MMR形成了复合体。与对照细胞相比，FAN1基因敲除的细胞对MNU的抵抗力更强，亚G1群体的出现和caspase-9的激活受到抑制。MNU处理后，FAN1以MLH1依赖的方式形成核灶，有的与MLH1灶和损伤部位产生的单链DNA(SsDNA)共存。在相同条件下，FANCD2也可形成核灶，但对于FAN1灶和单链DNA的形成是必不可少的。在FAN1基因敲除细胞中，MNU诱导的单链DNA的形成被显著抑制。因此，我们认为FAN1通过与MLH1的相互作用被负载在染色质上，并通过其核酸外切酶活性产生单链DNA，这有助于激活DNA损伤反应，进而诱导O6-Meg引发的细胞凋亡。
O6‐Methylguanines (O6‐meG), which are produced in DNA by the action of alkylating agents, are mutagenic and cytotoxic, and induce apoptosis in a mismatch repair (MMR) protein‐dependent manner. To understand the molecular mechanism of O6‐meG‐induced apoptosis, we performed functional analyses of FANCD2 and FANCI‐associated nuclease 1 (FAN1), which was identified as an interacting partner of MLH1. Immunoprecipitation analyses showed that FAN1 interacted with both MLH1 and MSH2 after treatment withN‐methyl‐N‐nitrosourea (MNU), indicating the formation of a FAN1‐MMR complex. In comparison with control cells,FAN1‐knockdown cells were more resistant to MNU, and the appearances of a sub‐G1population and caspase‐9 activation were suppressed. FAN1 formed nuclear foci in an MLH1‐dependent manner after MNU treatment, and some were colocalized with both MLH1 foci and single‐stranded DNA (ssDNA) created at damaged sites. Under the same condition, FANCD2 also formed nuclear foci, although it was dispensable for the formation of FAN1 foci and ssDNA. MNU‐induced formation of ssDNA was dramatically suppressed inFAN1‐knockdown cells. We therefore propose that FAN1 is loaded on chromatin through the interaction with MLH1 and produces ssDNA by its exonuclease activity, which contributes to the activation of the DNA damage response followed by the induction of apoptosis triggered by O6‐meG.
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影响因子：
64.5
作者：
FISHEL, R;LESCOE, MK;KOLODNER, R
通讯作者：
KOLODNER, R
影响因子：
16
作者：
Ken‐ichi Yoshioka;Y. Yoshioka;P. Hsieh
通讯作者：
Ken‐ichi Yoshioka;Y. Yoshioka;P. Hsieh
影响因子：
3.7
作者：
Fujikane R;Sanada M;Sekiguchi M;Hidaka M
通讯作者：
Hidaka M
烷基化诱导胚胎干细胞凋亡，其中 DNA 修复基因甲基转移酶已被基因靶向破坏。
影响因子：
4.7
作者：
Y. Tominaga;T. Tsuzuki;A. Shiraishi;H. Kawate;M. Sekiguchi
通讯作者：
M. Sekiguchi
DOI：
10.1126/science.aad5634
发表时间：
2016-02-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lachaud C;Moreno A;Marchesi F;Toth R;Blow JJ;Rouse J
通讯作者：
Rouse J