Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Mol Cell. 2010 Mar 26;37(6):879-86. doi: 10.1016/j.molcel.2010.01.036.
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.
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。
