FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway.
FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway.
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DOI：
10.1038/nsmb.1504
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发表时间：
2008-11
影响因子：
16.8
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中科院分区：
文献类型：
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响应于DNA损伤或复制叉应激，范可尼贫血（FA）途径被激活，导致FancD 2和FancI的单泛素化以及它们在病灶中的共定位。在这里，我们表明，在鸡DT 40细胞系统中，多个丙氨酸取代突变的6个保守和簇S/TQ基序的FancI在很大程度上废除monoubiquitination以及焦点形成的FancI和FancD 2，导致DNA修复功能的丧失。相反，在相同的6个残基上携带磷酸模拟突变的FancI诱导FancI和FancD 2的组成性单泛素化和焦点形成，并保护免受DNA链间交联剂的细胞杀伤和染色体断裂。我们认为FancI的多重磷酸化是激活FA通路的分子开关。对人FANCI中假定的磷酸化位点的突变分析表明，该开关在进化上是保守的。
In response to DNA damage or replication fork stress, the Fanconi anemia (FA) pathway is activated, leading to monoubiquitination of FancD2 and FancI and their co-localization in foci. Here we show that, in the chicken DT40 cell system, multiple alanine-substitution mutations in 6 conserved and clustered S/TQ motifs of FancI largely abrogate monoubiquitination as well as focus formation of both FancI and FancD2, resulting in loss of DNA repair function. Conversely, FancI carrying phospho-mimic mutations on the same 6 residues induces constitutive monoubiquitination and focus formation of FancI and FancD2, and protects against cell killing and chromosome breakage by DNA interstrand crosslinking agents. We propose that the multiple phosphorylation of FancI serves as a molecular switch in activation of the FA pathway. Mutational analysis of putative phosphorylation sites in human FANCI indicates that this switch is evolutionarily conserved.
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