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Cyclin-Dependent Kinase-Mediated Phosphorylation of FANCD2 Promotes Mitotic Fidelity.
Molecular and Cellular Biology ( IF 3.2 ) Pub Date : 2021-07-23 , DOI: 10.1128/mcb.00234-21
Juan A Cantres-Velez 1 , Justin L Blaize 1 , David A Vierra 1 , Rebecca A Boisvert 1 , Jada L Garzon 2 , Benjamin Piraino 1 , Winnie Tan 3 , Andrew J Deans 3 , Niall G Howlett 1
Affiliation  

Fanconi anemia (FA) is a rare genetic disease characterized by increased risk for bone marrow failure and cancer. The FA proteins function together to repair damaged DNA. A central step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins, which occurs upon exposure to DNA-damaging agents and during the S phase of the cell cycle. The regulatory mechanisms governing S-phase monoubiquitination, in particular, are poorly understood. In this study, we have identified a cyclin-dependent kinase (CDK) regulatory phosphosite (S592) proximal to the site of FANCD2 monoubiquitination. FANCD2 S592 phosphorylation was detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and by immunoblotting with an S592 phospho-specific antibody. Mutation of S592 leads to abrogated monoubiquitination of FANCD2 during the S phase. Furthermore, FA-D2 (FANCD2-/-) patient cells expressing S592 mutants display reduced proliferation under conditions of replication stress and increased mitotic aberrations, including micronuclei and multinucleated cells. Our findings describe a novel cell cycle-specific regulatory mechanism for the FANCD2 protein that promotes mitotic fidelity.

中文翻译:

细胞周期蛋白依赖性激酶介导的 FANCD2 磷酸化促进有丝分裂保真度。

范可尼贫血 (FA) 是一种罕见的遗传病,其特征是骨髓衰竭和癌症的风险增加。FA蛋白共同作用以修复受损的DNA。FA 通路激活的一个核心步骤是 FANCD2 和 FANCI 蛋白的单泛素化,这在暴露于 DNA 损伤剂和细胞周期的 S 期时发生。特别是对 S 期单泛素化的调控机制知之甚少。在这项研究中,我们确定了靠近 FANCD2 单泛素化位点的细胞周期蛋白依赖性激酶 (CDK) 调节磷酸位 (S592)。FANCD2 S592 磷酸化通过液相色谱-串联质谱 (LC-MS/MS) 和用 S592 磷酸特异性抗体进行免疫印迹来检测。S592 的突变导致 FANCD2 在 S 期期间的单泛素化被消除。此外,表达 S592 突变体的 FA-D2 (FANCD2-/-) 患者细胞在复制应激和有丝分裂畸变增加的条件下显示出增殖减少,包括微核和多核细胞。我们的研究结果描述了促进有丝分裂保真度的 FANCD2 蛋白的一种新的细胞周期特异性调节机制。
更新日期:2021-07-23
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