FANCD2与CtIP结合，并在DNA链间交联修复过程中调节DNA末端切除。
FANCD2 binds CtIP and regulates DNA-end resection during DNA interstrand crosslink repair.
作者信息
Unno Junya, Itaya Akiko, Taoka Masato, Sato Koichi, Tomida Junya, Sakai Wataru, Sugasawa Kaoru, Ishiai Masamichi, Ikura Tsuyoshi, Isobe Toshiaki, Kurumizaka Hitoshi, Takata Minoru
机构信息
Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan.
Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan; Japan Society for the Promotion of Science (JSPS), Tokyo 102-0083, Japan.
出版信息
Cell Rep. 2014 May 22;7(4):1039-47. doi: 10.1016/j.celrep.2014.04.005. Epub 2014 May 1.
The Fanconi anemia (FA) pathway is critically involved in the maintenance of hematopoietic stem cells and the suppression of carcinogenesis. A key FA protein, FANCD2, is monoubiquitinated and accumulates in chromatin in response to DNA interstrand crosslinks (ICLs), where it coordinates DNA repair through mechanisms that are still poorly understood. Here, we report that CtIP protein directly interacts with FANCD2. A region spanning amino acids 166 to 273 of CtIP and monoubiquitination of FANCD2 are both essential for the FANCD2-CtIP interaction and mitomycin C (MMC)-induced CtIP foci. Remarkably, both FANCD2 and CtIP are critical for MMC-induced RPA2 hyperphosphorylation, an event that accompanies end resection of double-strand breaks. Collectively, our results reveal a role of monoubiquitinated FANCD2 in end resection that depends on its binding to CtIP during ICL repair.
范可尼贫血（FA）通路在维持造血干细胞和抑制肿瘤发生过程中起着至关重要的作用。一种关键的FA蛋白FANCD2会发生单泛素化，并在响应DNA链间交联（ICL）时积聚在染色质中，其通过仍知之甚少的机制协调DNA修复。在此，我们报告CtIP蛋白直接与FANCD2相互作用。CtIP中跨越氨基酸166至273的区域以及FANCD2的单泛素化对于FANCD2-CtIP相互作用和丝裂霉素C（MMC）诱导的CtIP病灶均至关重要。值得注意的是，FANCD2和CtIP对于MMC诱导的RPA2过度磷酸化均至关重要，这一事件伴随着双链断裂的末端切除。总体而言，我们的结果揭示了单泛素化的FANCD2在末端切除中的作用，该作用在ICL修复过程中依赖于其与CtIP的结合。
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