Deficiency of FANCD2-Associated Nuclease KIAA1018/FAN1 Sensitizes Cells to Interstrand Crosslinking Agents
Deficiency of FANCD2-Associated Nuclease KIAA1018/FAN1 Sensitizes Cells to Interstrand Crosslinking Agents
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DOI：
10.1016/j.cell.2010.06.022
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发表时间：
2010-07-09
期刊：
影响因子：
64.5
通讯作者：
Jiricny, Josef
中科院分区：
文献类型：
--
作者：
Kratz, Katja;Schoepf, Barbara;Jiricny, Josef
顺铂和丝裂霉素C （MMC）的细胞毒性主要归因于它们在DNA中产生链间交联（ICLs）的能力，ICLs可以阻断复制分叉的进展。icl的加工需要范可尼贫血（Fanconi anemia， FA）途径、切除修复和翻译DNA合成（translesion DNA synthesis， TLS）。它还需要同源重组（HR）来修复被阻断的复制叉切割产生的双链断裂（DSBs）。KIAA1018是一种进化保守蛋白，具有n端泛素结合锌指（UBZ）和c端核酸酶结构域。KIAA1018是一种5‘ - bbbb3 ’外切酶和结构特异性内切酶，可优先切割50个皮瓣。与FA患者的细胞一样，缺乏KIAA1018的人细胞对icl诱导剂敏感，并表现出染色体不稳定性。KIAA1018通过其UBZ结构域与单泛素化的FANCD2相互作用募集DNA损伤，进一步加强了KIAA1018与FA通路的联系。因此，我们建议将KIAA1018命名为fancd2相关核酸酶FAN1。
Cytotoxicity of cisplatin and mitomycin C (MMC) is ascribed largely to their ability to generate interstrand crosslinks (ICLs) in DNA, which block the progression of replication forks. The processing of ICLs requires the Fanconi anemia (FA) pathway, excision repair, and translesion DNA synthesis (TLS). It also requires homologous recombination (HR), which repairs double-strand breaks (DSBs) generated by cleavage of the blocked replication forks. Here we describe KIAA1018, an evolutionarily conserved protein that has an N-terminal ubiquitin-binding zinc finger (UBZ) and a C-terminal nuclease domain. KIAA1018 is a 5' -> 3' exonuclease and a structure-specific endonuclease that preferentially incises 50 flaps. Like cells from FA patients, human cells depleted of KIAA1018 are sensitized to ICL-inducing agents and display chromosomal instability. The link of KIAA1018 to the FA pathway is further strengthened by its recruitment to DNA damage through interaction of its UBZ domain with monoubiquitylated FANCD2. We therefore propose to name KIAA1018 FANCD2-associated nuclease, FAN1.