MHF1-MHF2，一个含有组蛋白折叠结构域的蛋白复合物，通过 FANCM 参与范可尼贫血途径。
MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM.
机构信息
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
出版信息
Mol Cell. 2010 Mar 26;37(6):879-86. doi: 10.1016/j.molcel.2010.01.036.
Abstract
FANCM is a Fanconi anemia nuclear core complex protein required for the functional integrity of the FANC-BRCA pathway of DNA damage response and repair. Here we report the isolation and characterization of two histone-fold-containing FANCM-associated proteins, MHF1 and MHF2. We show that suppression of MHF1 expression results in (1) destabilization of FANCM and MHF2, (2) impairment of DNA damage-induced monoubiquitination and foci formation of FANCD2, (3) defective chromatin localization of FA nuclear core complex proteins, (4) elevated MMC-induced chromosome aberrations, and (5) sensitivity to MMC and camptothecin. We also provide biochemical evidence that MHF1 and MHF2 assemble into a heterodimer that binds DNA and enhances the DNA branch migration activity of FANCM. These findings reveal critical roles of the MHF1-MHF2 dimer in DNA damage repair and genome maintenance through FANCM.
摘要
FANCM 是范可尼贫血核核心复合物蛋白，是 DNA 损伤反应和修复中 FANC-BRCA 途径功能完整性所必需的。在这里，我们报告了两个含有组蛋白折叠结构的 FANCM 相关蛋白 MHF1 和 MHF2 的分离和特性。我们表明，抑制 MHF1 的表达会导致：（1）FANCM 和 MHF2 的不稳定性；（2）DNA 损伤诱导的 FANCD2 单泛素化和焦点形成受损；（3）FA 核核心复合物蛋白的染色质定位缺陷；（4）MMC 诱导的染色体畸变增加；（5）对 MMC 和喜树碱敏感。我们还提供了生化证据，表明 MHF1 和 MHF2 组装成异二聚体，结合 DNA，并增强 FANCM 的 DNA 分支迁移活性。这些发现揭示了 MHF1-MHF2 二聚体通过 FANCM 在 DNA 损伤修复和基因组维护中的关键作用。
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