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首页> 外文期刊>Journal of Molecular Biology >Analysis of a FANCE Splice Isoform in Regard to DNA Repair
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Analysis of a FANCE Splice Isoform in Regard to DNA Repair

机译：关于DNA修复的FENCE剪接同工型分析

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The FANC-BRCA DNA repair pathway is activated in response to interstrand crosslinks formed in DNA. A homozygous mutation in 1 of the 17 Fanconi anemia (FA) genes results in malfunctions of this pathway and development of FA syndrome. The integrity of this protein network is essential for good maintenance of DNA repair process and genome stability. Following the identification of an alternatively splice isoform of FANCE (Fanconi anemia complementation group E) significantly expressed in breast cancer individuals from high-risk non-BRCA1/2 families, we studied the impact of this FANCE splice isoform (FANCE Delta 4) on DNA repair processes. We have demonstrated that FANCE Delta 4 mRNA was efficiently translated into a functional protein and expressed in normal and breast cancer cell lines. Following treatment with the crosslinking agent mitomycin C, EUFA130 (FANCE-deficient) cells infected with FANCE Delta 4 were blocked into G2/M phase, while cell survival was significantly reduced compared with FANCE-infected EUFA130 cells. In addition, FANCE Delta 4 did not allow FANCD2 and FANCI monoubiquitination, which represents a crucial step of the FANC-BRCA functional pathway. As observed for FANCE wild-type protein, localization of FANCE Delta 4 protein was confined to the nucleus following mitomycin C treatment. Although FANCE Delta 4 protein showed interaction with FANCE, FANCE Delta 4 did not support normal function of FANCE protein in this pathway and could have deleterious effects on FANCE protein activity. We have demonstrated that FANCE Delta 4 seems to act as a regulator of FANCD2 protein expression level by promoting its degradation. This study highlights the importance of an efficient regulation of alternative splicing expression of FA genes for proper DNA repair. (C) 2015 Elsevier Ltd. All rights reserved.
机译：响应DNA中形成的链间交联，激活了FANC-BRCA DNA修复途径。 17个Fanconi贫血（FA）基因中的1个纯合突变导致该途径功能异常和FA综合征的发展。该蛋白质网络的完整性对于良好地维持DNA修复过程和基因组稳定性至关重要。在鉴定出在高危非BRCA1 / 2家族的乳腺癌个体中显着表达的FANCE替代剪接同工型（Fanconi贫血补充组E）后，我们研究了该FANCE剪接同工型（FANCE Delta 4）对DNA的影响维修过程。我们已经证明，FANCE Delta 4 mRNA被有效地翻译成功能蛋白，并在正常和乳腺癌细胞系中表达。用交联剂丝裂霉素C处理后，被FANCE Delta 4感染的EUFA130（FANCE缺陷型）细胞被阻断进入G2 / M期，而与被FANCE感染的EUFA130细胞相比，细胞存活率显着降低。此外，FANCE Delta 4不允许FANCD2和FANCI单泛素化，这是FANC-BRCA功能途径的关键步骤。如对于FANCE野生型蛋白观察到的那样，在丝裂霉素C处理后，FANCE Delta 4蛋白的定位局限于核内。尽管FANCE Delta 4蛋白显示出与FANCE的相互作用，但FANCE Delta 4在该途径中不支持FANCE蛋白的正常功能，并且可能对FANCE蛋白活性产生有害影响。我们已经证明FANCE Delta 4似乎通过促进其降解来充当FANCD2蛋白表达水平的调节剂。这项研究强调了有效调节FA基因的选择性剪接表达对适当的DNA修复的重要性。 （C）2015 Elsevier Ltd.保留所有权利。

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