Flap endonuclease overexpression drives genome instability and DNA damage hypersensitivity in a PCNA-dependent manner.
Flap endonuclease overexpression drives genome instability and DNA damage hypersensitivity in a PCNA-dependent manner.
复制标题
DOI：
10.1093/nar/gky313
复制
发表时间：
2018-06-20
影响因子：
14.9
通讯作者：
Bielinsky AK
中科院分区：
文献类型：
--
作者：
Becker JR;Gallo D;Leung W;Croissant T;Thu YM;Nguyen HD;Starr TK;Brown GW;Bielinsky AK
FEN1在多种癌症类型中均有过表达，是预后不良的标志。为了更好地理解FEN1过度表达的细胞后果，我们利用了它的酿酒酵母同源物RAD27的模型。在这个系统中，我们发现翻盖核酸内切酶的过表达阻碍了复制分叉的进展，并导致细胞在S中期积累。伴随而来的是检验点蛋白RAD53和组蛋白H2A-S129的磷酸化增加。过表达RAD27的细胞对DNA损伤剂治疗高度敏感，并且在复制钳制增殖细胞核抗原(增殖细胞核抗原)的赖氨酸164的泛素化方面存在缺陷。当过表达的Rad27和增殖细胞核抗原之间的相互作用被阻断时，这些效应被逆转，这表明所观察到的表型与DNA复制问题有关。过表达RAD27的细胞也表现出对相扑连接酶SIZ1和MMS21生存能力的意外依赖。重要的是，我们发现FEN1在人类细胞中的过度表达也导致了CHK1、CHK2、RPA32和组蛋白H2AX的磷酸化，这些都是基因组不稳定的标志。我们的数据表明，在酵母和人类细胞中，翻盖核酸内切酶的过度表达是基因组不稳定的驱动因素，这种不稳定损害了DNA复制，这种方式依赖于它与增殖细胞核抗原的相互作用。
Overexpression of the flap endonuclease FEN1 has been observed in a variety of cancer types and is a marker for poor prognosis. To better understand the cellular consequences of FEN1 overexpression we utilized a model of its Saccharomyces cerevisiae homolog, RAD27. In this system, we discovered that flap endonuclease overexpression impedes replication fork progression and leads to an accumulation of cells in mid-S phase. This was accompanied by increased phosphorylation of the checkpoint kinase Rad53 and histone H2A-S129. RAD27 overexpressing cells were hypersensitive to treatment with DNA damaging agents, and defective in ubiquitinating the replication clamp proliferating cell nuclear antigen (PCNA) at lysine 164. These effects were reversed when the interaction between overexpressed Rad27 and PCNA was ablated, suggesting that the observed phenotypes were linked to problems in DNA replication. RAD27 overexpressing cells also exhibited an unexpected dependence on the SUMO ligases SIZ1 and MMS21 for viability. Importantly, we found that overexpression of FEN1 in human cells also led to phosphorylation of CHK1, CHK2, RPA32 and histone H2AX, all markers of genome instability. Our data indicate that flap endonuclease overexpression is a driver of genome instability in yeast and human cells that impairs DNA replication in a manner dependent on its interaction with PCNA.
登录
查看更多内容
影响因子：
14.9
作者：
Bakr A;Oing C;Köcher S;Borgmann K;Dornreiter I;Petersen C;Dikomey E;Mansour WY
通讯作者：
Mansour WY
影响因子：
16
作者：
Guo, Zhigang;Kanjanapangka, Julie;Liu, Na;Liu, Songbai;Liu, Changwei;Wu, Zhenxing;Wang, Yingjie;Loh, Tiffany;Kowolik, Claudia;Jamsen, Joonas;Zhou, Mian;Khue Truong;Chen, Yuan;Zheng, Li;Shen, Binghui
通讯作者：
Shen, Binghui
影响因子：
64.8
作者：
Downs, JA;Lowndes, NF;Jackson, SP
通讯作者：
Jackson, SP
影响因子：
4.3
作者：
Becker, Jordan R.;Hai Dang Nguyen;Bielinsky, Anja-Katrin
通讯作者：
Bielinsky, Anja-Katrin
靶向 DNA Flap 核酸内切酶 1 阻止乳腺癌进展
影响因子：
11.1
作者：
He, Lingfeng;Zhang, Yilan;Sun, Hongfang;Jiang, Feng;Yang, Huan;Wu, Huan;Zhou, Ting;Hu, Sencai;Kathera, Chandra Sekhar;Wang, Xiaojun;Chen, Haoyan;Li, Hongzhi;Shen, Binghui;Zhu, Yongqiang;Guo, Zhigang
通讯作者：
Guo, Zhigang