Russell Beatriz, Bhattacharyya Saumitri, Keirsey Jeremy, Sandy April, Grierson Patrick, Perchiniak Erin, Kavecansky Juraj, Acharya Samir, Groden Joanna
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio 45229, USA.
Cancer Res. 2011 Jan 15;71(2):561-71. doi: 10.1158/0008-5472.CAN-10-1727. Epub 2011 Jan 11.
Cells deficient in the recQ-like helicase BLM are characterized by chromosome changes that suggest the disruption of normal mechanisms needed to resolve recombination intermediates and to maintain chromosome stability. Human BLM and topoisomerase IIα interact directly via amino acids 489-587 of BLM and colocalize predominantly in late G2 and M phases of the cell cycle. Deletion of this region does not affect the inherent in vitro helicase activity of BLM but inhibits the topoisomerase IIα-dependent enhancement of its activity, based on the analysis of specific DNA substrates that represent some recombination intermediates. Deletion of the interaction domain from BLM fails to correct the elevated chromosome breakage of transfected BLM-deficient cells. Our results demonstrate that the BLM-topoisomerase IIα interaction is important for preventing chromosome breakage and elucidate a DNA repair mechanism that is critical to maintain chromosome stability in cells and to prevent tumor formation.
缺乏类recQ解旋酶BLM的细胞具有染色体变化的特征，这些变化表明正常机制受到破坏，而这些机制是解决重组中间体和维持染色体稳定性所必需的。人BLM与拓扑异构酶IIα通过BLM的489 - 587位氨基酸直接相互作用，并主要在细胞周期的G2晚期和M期共定位。基于对代表一些重组中间体的特定DNA底物的分析，该区域的缺失不影响BLM固有的体外解旋酶活性，但会抑制拓扑异构酶IIα对其活性的依赖性增强。从BLM中删除相互作用结构域未能纠正转染的BLM缺陷细胞中升高的染色体断裂。我们的结果表明，BLM - 拓扑异构酶IIα相互作用对于防止染色体断裂很重要，并阐明了一种DNA修复机制，该机制对于维持细胞中的染色体稳定性和预防肿瘤形成至关重要。
