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首页> 外文期刊>Molecular and Cellular Biology >APLF (C2orf13) Is a Novel Human Protein Involved in the Cellular Response to Chromosomal DNA Strand Breaks
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APLF (C2orf13) Is a Novel Human Protein Involved in the Cellular Response to Chromosomal DNA Strand Breaks

机译：APLF（C2orf13）是一种新型的人类蛋白质，参与细胞对染色体DNA链断裂的反应。

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Aprataxin and polynucleotide kinase (PNK) are DNA end processing factors that are recruited into the DNA single- and double-strand break repair machinery through phosphorylation-specific interactions with XRCC1 and XRCC4, respectively. These interactions are mediated through a divergent class of forkhead-associated (FHA) domain that binds to peptide sequences in XRCC1 and XRCC4 that are phosphorylated by casein kinase 2 (CK2). Here, we identify the product of the uncharacterized open reading frame C2orf13 as a novel member of this FHA domain family of proteins and we denote this protein APLF (aprataxin- and PNK-like factor). We show that APLF interacts with XRCC1 in vivo and in vitro in a manner that is stimulated by CK2. Yeast two-hybrid analyses suggest that APLF also interacts with the double-strand break repair proteins XRCC4 and XRCC5 (Ku86). We also show that endogenous and yellow fluorescent protein-tagged APLF accumulates at sites of H2O2 or UVA laser-induced chromosomal DNA damage and that this is achieved through at least two mechanisms: one that requires the FHA domain-mediated interaction with XRCC1 and a second that is independent of XRCC1 but requires a novel type of zinc finger motif located at the C terminus of APLF. Finally, we demonstrate that APLF is phosphorylated in a DNA damage- and ATM-dependent manner and that the depletion of APLF from noncycling human SH-SY5Y neuroblastoma cells reduces rates of chromosomal DNA strand break repair following ionizing radiation. These data identify APLF as a novel component of the cellular response to DNA strand breaks in human cells.
机译：Aprataxin和多核苷酸激酶（PNK）是DNA末端加工因子，它们分别通过与XRCC1和XRCC4的磷酸化特异性相互作用而被募集到DNA单链和双链断裂修复机制中。这些相互作用通过与叉头相关（FHA）域不同的类介导，该域与酪蛋白激酶2（CK2）磷酸化的XRCC1和XRCC4中的肽序列结合。在这里，我们将未鉴定的开放阅读框C2orf13的产物鉴定为该FHA结构域蛋白家族的新成员，并称该蛋白为APLF（ a prataxin-和 P NK- l ike f actor）。我们显示，APLF与XRCC1在体内和体外以CK2刺激的方式相互作用。酵母两杂交分析表明，APLF还与双链断裂修复蛋白XRCC4和XRCC5（Ku86）相互作用。我们还显示，内源性和黄色荧光蛋白标记的APLF聚集在H 2 O 2 或UVA激光诱导的染色体DNA损伤的位点，并且至少可以通过两种机制：一种需要FHA结构域与XRCC1介导的相互作用，第二种独立于XRCC1但需要位于APLF C末端的新型锌指基序。最后，我们证明APLF以DNA损伤和ATM依赖性方式被磷酸化，并且从非循环人类SH-SY5Y神经母细胞瘤细胞中消耗APLF会降低电离辐射后染色体DNA链断裂修复的速率。这些数据将APLF鉴定为对人类细胞中DNA链断裂的细胞反应的新成分。

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