The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways
The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways
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DOI：
10.1074/jbc.m109.007690
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发表时间：
2009-09-18
影响因子：
4.8
通讯作者：
Hoatlin, Maureen E.
中科院分区：
文献类型：
--
作者：
Sobeck, Alexandra;Stone, Stacie;Hoatlin, Maureen E.
基因组稳定性需要功能性范可尼贫血（Fanconi anemia， FA）通路，该通路由上游“核心复合体”（FA蛋白a /B/C/E/F/G/L/M）组成，介导下游靶点FANCD2和FANCI的单泛素化。在FA核心复合体成员中，FANCM具有针对复制相关DNA结构的加工活动，这表明FANCM在复制过程中起着至关重要的作用。利用爪蟾卵提取物，分析了FANCM在复制和DNA损伤应答中的功能。xFANCM以复制依赖的方式结合染色质，并在DNA损伤结构的响应中磷酸化。染色质结合和DNA损伤诱导的xFANCM磷酸化部分是由下游FA通路蛋白FANCD2介导的。此外，FANCM的磷酸化和染色质募集是由DNA损伤反应中的两个主要参与者调节的：细胞周期检查点激酶ATR和ATM。我们的研究结果表明，FANCM的功能在DNA损伤反应中受到FA和非FA途径的控制。
Genomic stability requires a functional Fanconi anemia (FA) pathway composed of an upstream "core complex" (FA proteins A/B/C/E/F/G/L/M) that mediates monoubiquitination of the downstream targets FANCD2 and FANCI. Unique among FA core complex members, FANCM has processing activities toward replication-associated DNA structures, suggesting a vital role for FANCM during replication. Using Xenopus egg extracts, we analyzed the functions of FANCM in replication and the DNA damage response. xFANCM binds chromatin in a replication-dependent manner and is phosphorylated in response to DNA damage structures. Chromatin binding and DNA damage-induced phosphorylation of xFANCM are mediated in part by the downstream FA pathway protein FANCD2. Moreover, phosphorylation and chromatin recruitment of FANCM is regulated by two mayor players in the DNA damage response: the cell cycle checkpoint kinases ATR and ATM. Our results indicate that functions of FANCM are controlled by FA- and non-FA pathways in the DNA damage response.