Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction.
Fanconi anemia complementation group FANCD2 protein serine 331 phosphorylation is important for fanconi anemia pathway function and BRCA2 interaction.
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DOI：
10.1158/0008-5472.can-09-2312
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发表时间：
2009-11-15
期刊：
影响因子：
11.2
通讯作者：
Kupfer GM
中科院分区：
文献类型：
--
作者：
Zhi G;Wilson JB;Chen X;Krause DS;Xiao Y;Jones NJ;Kupfer GM
范可尼贫血（FA）是一种具有至少13个互补基团（FANCA、-B、-C、-D1、-D2、-E、-F、-G、-I、-J、-L、-M、-N）的癌症易感性遗传性骨髓衰竭和癌症易感性综合征。我们的实验室以前已经描述了几个调节磷酸化事件的核心复合体成员蛋白FANCG和FANCA的磷酸化。在这项研究中，我们报告了一个新的磷酸化位点S331的FANCD 2，关键的下游球员的FA途径。S331的磷酸化对于其DNA损伤诱导的单泛素化、对DNA交联剂的抗性以及与FANCD 1/BRCA 2的体内相互作用是重要的。S331处的磷酸化模拟突变将所有这些表型恢复为野生型。体外和体内实验表明，S331的磷酸化是由CHK 1介导的，CHK 1是FA DNA修复途径中涉及的S期检查点激酶。
Fanconi Anemia (FA) is a cancer-prone inherited bone marrow failure and cancer susceptibility syndrome with at least 13 complementation groups (FANCA, -B, -C, -D1, -D2, -E,-F, -G, -I, -J, -L, -M, -N). Our laboratory has previously described several regulatory phosphorylation events for core complex member proteins FANCG and FANCA by phosphorylation. In this study we report a novel phosphorylation site S331 of FANCD2, the pivotal downstream player of the FA pathway. Phosphorylation of S331 is important for its DNA damage inducible monoubiquitylation, resistance to DNA crosslinkers and in vivo interaction with FANCD1/BRCA2. A phosphomimetic mutation at S331 restores all of these phenotypes to wild type. In vitro and in vivo experiments show phosphorylation of S331 is mediated by CHK1, the S phase checkpoint kinase implicated in the FA DNA repair pathway.