The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway
The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway
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DOI：
10.1016/j.molcel.2005.01.008
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发表时间：
2005-02-04
期刊：
影响因子：
16
通讯作者：
Bernards, R
中科院分区：
文献类型：
--
作者：
Nijman, SMB;Huang, TT;Bernards, R
蛋白质泛素化和去泛素化是涉及许多细胞途径调节的动态过程。范可尼贫血（FA）蛋白FANCD 2的单泛素化似乎在DNA损伤的修复中至关重要，因为FA中突变的许多蛋白质是FANCD 2泛素化所必需的。通过筛选基因家族RNAi文库，我们确定了去泛素化酶USP1作为范可尼贫血途径的新组分。USP 1的抑制导致monoubiquitinated FANCD 2的过度积累。此外，USP 1与FANCD 2物理缔合，并且蛋白质在DNA损伤后共定位于染色质中。最后，在USP1敲低细胞中对交联剂诱导的染色体畸变的分析表明其在DNA修复中的作用。我们认为，当细胞退出S期或DNA损伤损伤后重新开始循环时，USP1使FANCD 2去泛素化，并可能通过回收FANCD 2在FA途径中发挥关键作用。
Protein ubiquitination and deubiquitination are dynamic processes implicated in the regulation of numerous cellular pathways. Monoubiquitination of the Fanconi anemia (FA) protein FANCD2 appears to be critical in the repair of DNA damage because many of the proteins that are mutated in FA are required for FANCD2 ubiquitination. By screening a gene family RNAi library, we identify the deubiquitinating enzyme USP1 as a novel component of the Fanconi anemia pathway. Inhibition of USP1 leads to hyperaccumulation of monoubiquitinated FANCD2. Furthermore, USP1 physically associates with FANCD2, and the proteins colocalize in chromatin after DNA damage. Finally, analysis of crosslinker-induced chromosomal aberrations in USP1 knockdown cells suggests a role in DNA repair. We propose that USP1 deubiquitinates FANCD2 when cells exit S phase or recommence cycling after a DNA damage insult and may play a critical role in the FA pathway by recycling FANCD2.