The human DEK oncogene regulates DNA damage response signaling and repair.
The human DEK oncogene regulates DNA damage response signaling and repair.
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DOI：
10.1093/nar/gkr454
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发表时间：
2011-09-01
影响因子：
14.9
通讯作者：
Wells SI
中科院分区：
文献类型：
--
作者：
Kavanaugh GM;Wise-Draper TM;Morreale RJ;Morrison MA;Gole B;Schwemberger S;Tichy ED;Lu L;Babcock GF;Wells JM;Drissi R;Bissler JJ;Stambrook PJ;Andreassen PR;Wiesmüller L;Wells SI
人类DEK基因在人类癌症中经常过度表达，有时还会被扩增。与致癌功能一致，DEK基因敲除小鼠对化学诱导的乳头状瘤形成具有部分抵抗力。此外，在体外，DEK基因敲除使癌细胞对DNA损伤剂敏感，并通过依赖和不依赖于P53的机制诱导细胞死亡。在此，我们报告了DEK对于DNA双链断裂修复的重要作用。根据对γ、H_2AX和FANCD2的检测，人类癌细胞系和异种移植中DEK的耗竭足以诱导DNA损伤反应。H_2AX的磷酸化分别伴随着ATM和DNA-PK通路的激活和抑制。在原代DEK基因敲除的小鼠胚胎成纤维细胞(MEF)中也观察到了类似的DNA损伤反应，并伴随着DNA损伤水平的增加和对遗传毒性应激的过度诱导衰老。重要的是，与野生型相比，DEK基因敲除的MEF在非同源末端连接(NHEJ)中显示出明显的缺陷。综上所述，这些数据显示了DEK和DNA损伤反应信号通路之间的新的分子联系，并表明DEK有助于DNA修复。
The human DEK gene is frequently overexpressed and sometimes amplified in human cancer. Consistent with oncogenic functions, Dek knockout mice are partially resistant to chemically induced papilloma formation. Additionally, DEK knockdown in vitro sensitizes cancer cells to DNA damaging agents and induces cell death via p53-dependent and -independent mechanisms. Here we report that DEK is important for DNA double-strand break repair. DEK depletion in human cancer cell lines and xenografts was sufficient to induce a DNA damage response as assessed by detection of γH2AX and FANCD2. Phosphorylation of H2AX was accompanied by contrasting activation and suppression, respectively, of the ATM and DNA-PK pathways. Similar DNA damage responses were observed in primary Dek knockout mouse embryonic fibroblasts (MEFs), along with increased levels of DNA damage and exaggerated induction of senescence in response to genotoxic stress. Importantly, Dek knockout MEFs exhibited distinct defects in non-homologous end joining (NHEJ) when compared to their wild-type counterparts. Taken together, the data demonstrate new molecular links between DEK and DNA damage response signaling pathways, and suggest that DEK contributes to DNA repair.
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DOI：
10.1016/j.tig.2008.08.007
发表时间：
2008-11
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
McVey M;Lee SE
通讯作者：
Lee SE
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
4
作者：
Kim, Dong-Wook;Chae, Jung-Il;Seo, Sang-Beom
通讯作者：
Seo, Sang-Beom
影响因子：
4.8
作者：
Cleary, J;Sitwala, KV;Markovitz, DM
通讯作者：
Markovitz, DM
影响因子：
3.5
作者：
Ko, Soo-Il;Lee, In-Seon;Seo, Sang-Beom
通讯作者：
Seo, Sang-Beom