Topoisomerase IIalpha maintains genomic stability through decatenation G(2) checkpoint signaling.
Topoisomerase IIalpha maintains genomic stability through decatenation G(2) checkpoint signaling.
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DOI：
10.1038/onc.2010.232
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发表时间：
2010-08-26
期刊：
影响因子：
8
通讯作者：
Kaufmann, W. K.
中科院分区：
文献类型：
--
作者：
Bower, J. J.;Karaca, G. F.;Zhou, Y.;Simpson, D. A.;Cordeiro-Stone, M.;Kaufmann, W. K.
拓扑异构酶Ⅱ α（Topoisomerase Ⅱ α，topoIIα）是哺乳动物中一种重要的DNA拓扑修饰酶，在有丝分裂过程中染色体分离中起重要作用。以前的研究表明，抑制topoII decatenatory活动触发G2检查点的反应，延迟有丝分裂进入由于不足的子染色单体的decatenation。在这里，我们研究了topoIIα和topoIIβ对细胞提取物中的脱连环活性、DNA损伤和脱连环G2检查点功能以及p16 INK 4A等位基因丢失和获得频率的影响。在二倍体人成纤维细胞系中，通过siRNA耗尽topoIIα与严重降低的decatenatory活性、延迟从G2到有丝分裂的进展以及对topoII催化抑制剂ICRF-193诱导的G2停滞不敏感相关。此外，topoIIα缺失细胞的间期核显示肿瘤抑制基因位点p16 INK 4A的丢失和获得频率增加。本研究表明，topoIIα蛋白是去连环化G2检查点功能所必需的，去连环化和去连环化G2检查点的失活导致染色体异常分离和基因组不稳定。
Topoisomerase IIα (topoIIα) is an essential mammalian enzyme that topologically modifies DNA and is required for chromosome segregation during mitosis. Previous research suggests that inhibition of topoII decatenatory activity triggers a G2 checkpoint response, which delays mitotic entry due to insufficient decatenation of daughter chromatids. Here we examine the effects of both topoIIα and topoIIβ on decatenatory activity in cell extracts, DNA damage and decatenation G2 checkpoint function, and the frequencies of p16INK4A allele loss and gain. In diploid human fibroblast lines, depletion of topoIIα by siRNA was associated with severely reduced decatenatory activity, delayed progression from G2 into mitosis, and insensitivity to G2 arrest induced by the topoII catalytic inhibitor ICRF-193. Furthermore, interphase nuclei of topoIIα-depleted cells displayed increased frequencies of losses and gains of the tumor suppressor genetic locus p16INK4A. This study demonstrates that the topoIIα protein is required for decatenation G2 checkpoint function, and inactivation of decatenation and the decatenation G2 checkpoint leads to abnormal chromosome segregation and genomic instability.
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影响因子：
3.7
作者：
Díaz-Martínez LA;Giménez-Abián JF;Azuma Y;Guacci V;Giménez-Martín G;Lanier LM;Clarke DJ
通讯作者：
Clarke DJ
DOI：
10.1038/nrm2718
发表时间：
2009-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.4161/cc.9.8.11470
发表时间：
2010-04-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Bower JJ;Zhou Y;Zhou T;Simpson DA;Arlander SJ;Paules RS;Cordeiro-Stone M;Kaufmann WK
通讯作者：
Kaufmann WK
影响因子：
64.8
作者：
DOWNES, CS;CLARKE, DJ;JOHNSON, RT
通讯作者：
JOHNSON, RT
影响因子：
4.8
作者：
Jensen, LH;Nitiss, KC;Nitiss, JL
通讯作者：
Nitiss, JL