Lou Zhenkun, Minter-Dykhouse Katherine, Chen Junjie
Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Nat Struct Mol Biol. 2005 Jul;12(7):589-93. doi: 10.1038/nsmb953. Epub 2005 Jun 19.
The tumor suppressor BRCA1 has an important function in the maintenance of genomic stability. Increasing evidence suggests that BRCA1 regulates cell cycle checkpoints and DNA repair after DNA damage. However, little is known about its normal function in the absence of DNA damage. Here we show that BRCA1 interacts and colocalizes with topoisomerase IIalpha in S phase cells. Similar to cells treated with the topoisomerase IIalpha inhibitor ICRF-193, BRCA1-deficient cells show lagging chromosomes, indicating a defect in DNA decatenation and chromosome segregation. More directly, BRCA1 deficiency results in defective DNA decatenation in vitro. Finally, topoisomerase IIalpha is ubiquitinated in a BRCA1-dependent manner, and topoisomerase IIalpha ubiquitination correlates with higher DNA decatenation activity. Together these results suggest an important role of BRCA1 in DNA decatenation and reveal a previously unknown function of BRCA1 in the maintenance of genomic stability.
肿瘤抑制因子BRCA1在维持基因组稳定性方面具有重要功能。越来越多的证据表明，BRCA1在DNA损伤后调节细胞周期检查点和DNA修复。然而，在没有DNA损伤的情况下，其正常功能却知之甚少。在此我们表明，BRCA1在S期细胞中与拓扑异构酶IIα相互作用并共定位。与用拓扑异构酶IIα抑制剂ICRF-193处理的细胞相似，BRCA1缺陷型细胞显示出滞后染色体，表明在DNA解连环和染色体分离方面存在缺陷。更直接地说，BRCA1缺陷在体外导致DNA解连环缺陷。最后，拓扑异构酶IIα以BRCA1依赖的方式被泛素化，并且拓扑异构酶IIα泛素化与更高的DNA解连环活性相关。这些结果共同表明BRCA1在DNA解连环中具有重要作用，并揭示了BRCA1在维持基因组稳定性方面以前未知的功能。
