The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks
The Fanconi anemia protein FANCM can promote branch migration of Holliday junctions and replication forks
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DOI：
10.1016/j.molcel.2007.11.032
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发表时间：
2008-01-18
期刊：
影响因子：
16
通讯作者：
Constantinou, Angelos
中科院分区：
文献类型：
--
作者：
Gari, Kerstin;Decaillet, Chantal;Constantinou, Angelos
范可尼贫血（FA）是一种遗传异质性癌症易感性疾病，与染色体不稳定性和细胞对DNA交联剂的超敏反应有关。FA途径被怀疑在细胞对DNA复制应激的反应中起着至关重要的作用。然而，在分子水平上，大多数FA蛋白的功能是未知的。FANCM显示DNA依赖性ATP酶活性，并促进DNA三链体的解离，但这种活性的生理意义仍然难以捉摸。在这里，我们表明，纯化的FANCM结合霍利迪连接和复制叉具有高度特异性，并促进迁移的连接点在ATP酶依赖的方式。此外，我们提供的证据表明，FANCM可以解离大的重组中间体，通过分支迁移霍利迪路口通过2.6 kb的DNA。我们的数据表明FANCM在DNA加工中的直接作用，与目前认为FA蛋白在停滞的复制叉处协调DNA修复的观点一致。
Fanconi anemia (FA) is a genetically heterogeneous cancer-prone disorder associated with chromosomal instability and cellular hypersensitivity to DNA crosslinking agents. The FA pathway is suspected to play a crucial role in the cellular response to DNA replication stress. At a molecular level, however, the function of most of the FA proteins is unknown. FANCM displays DNA-dependent ATPase activity and promotes the dissociation of DNA triplexes, but the physiological significance of this activity remains elusive. Here we show that purified FANCM binds to Holliday junctions and replication forks with high specificity and promotes migration of their junction point in an ATPase-dependent manner. Furthermore, we provide evidence that FANCM can dissociate large recombination intermediates, via branch migration of Holliday junctions through 2.6 kb of DNA. Our data suggest a direct role for FANCM in DNA processing, consistent with the current view that FA proteins coordinate DNA repair at stalled replication forks.