The Analysis of Pendolino (peo) Mutants Reveals Differences in the Fusigenic Potential among Drosophila Telomeres.
The Analysis of Pendolino (peo) Mutants Reveals Differences in the Fusigenic Potential among Drosophila Telomeres.
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Pendolino（PEO）突变体的分析揭示了果蝇端粒之间熔融潜能的差异。
DOI：
10.1371/journal.pgen.1005260
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发表时间：
2015-06
期刊：
影响因子：
4.5
通讯作者：
Gatti M
中科院分区：
文献类型：
--
作者：
Cenci G;Ciapponi L;Marzullo M;Raffa GD;Morciano P;Raimondo D;Burla R;Saggio I;Gatti M
果蝇端粒是序列独立的结构，通过转座到三种特殊逆转录元件（HeT-A、TART 和 TAHRE；统称为 HTT）的染色体末端而不是端粒酶活性来维持。果蝇端粒受到仅在端粒定位和发挥作用的末端蛋白复合物 (HOAP-HipHop-Moi-Ver) 和不提供端粒特异性功能的非末端蛋白的保护。尽管所有果蝇端粒均以 HTT 阵列终止并由末端封端，但它们的亚端粒染色质类型有所不同； Y、XR和4L HTT与组成型异染色质并列，而XL、2L、2R、3L和3R HTT与TAS重复序列连接； 4R HTT 与具有常染色质和异染色质共同特征的染色质相关。在这里，我们发现 pendolino (peo) 的突变会导致端粒融合 (TF)。对几个 peo 突变体组合的分析表明，这些 TF 优先涉及 Y、XR 和第 4 号染色体端粒，这是迄今为止在其他 10 个端粒加帽突变体中从未观察到的 TF 模式。 peo 编码与 E2 变体泛素结合酶同源的非末端蛋白。 Peo蛋白直接与末端蛋白成分相互作用，但peo突变不影响HOAP、Moi、Ver和HP1a的端粒定位，这表明peo依赖性端粒融合表型并不是由于染色体末端末端蛋白丢失所致。 peo 突变体在 DNA 复制和 PCNA 募集方面也存在缺陷。然而，我们的结果表明 DNA 复制的一般缺陷无法在果蝇细胞中诱导 TF。因此，我们假设 Peo 耗尽细胞中的 DNA 复制导致集中在异染色质相关端粒中的特定融合损伤。或者，Peo 可能发挥 DNA 复制和端粒加帽独立所需的双重功能。端粒是保护染色体末端免于不完全复制、降解和端到端融合的特殊结构。端粒结构或维护的异常会促进多种人类疾病，包括过早衰老和癌症。尽管所有人类端粒都含有相同的 DNA 序列，但它们在亚端粒区域或亚端粒方面彼此不同。最近的研究表明，人类亚端粒控制端粒复制，这些结构的异常可能导致局部染色体不稳定和疾病。然而，目前人们对亚端粒和端粒之间的关系知之甚少。在这里，我们使用果蝇果蝇作为模型系统解决了这个问题。果蝇亚端粒彼此非常不同，因为它们含有不同类型的染色质。我们发现，称为 pendolino (peo) 的基因突变会导致端粒融合 (TF)，并且这些融合优先涉及与紧密堆积的染色质形式（称为异染色质）相关的端粒。有趣的是，迄今为止在果蝇中描述的 10 个具有 TF 的突变体中没有一个显示出在 peo 突变体中观察到的 TF 模式。因此，我们的数据首次证明亚端粒可以影响端粒融合。我们相信这些结果将激发对亚端粒在维持基因组稳定性中的作用的进一步研究。
Drosophila telomeres are sequence-independent structures that are maintained by transposition to chromosome ends of three specialized retroelements (HeT-A, TART and TAHRE; collectively designated as HTT) rather than telomerase activity. Fly telomeres are protected by the terminin complex (HOAP-HipHop-Moi-Ver) that localizes and functions exclusively at telomeres and by non-terminin proteins that do not serve telomere-specific functions. Although all Drosophila telomeres terminate with HTT arrays and are capped by terminin, they differ in the type of subtelomeric chromatin; the Y, XR, and 4L HTT are juxtaposed to constitutive heterochromatin, while the XL, 2L, 2R, 3L and 3R HTT are linked to the TAS repetitive sequences; the 4R HTT is associated with a chromatin that has features common to both euchromatin and heterochromatin. Here we show that mutations in pendolino (peo) cause telomeric fusions (TFs). The analysis of several peo mutant combinations showed that these TFs preferentially involve the Y, XR and 4th chromosome telomeres, a TF pattern never observed in the other 10 telomere-capping mutants so far characterized. peo encodes a non-terminin protein homologous to the E2 variant ubiquitin-conjugating enzymes. The Peo protein directly interacts with the terminin components, but peo mutations do not affect telomeric localization of HOAP, Moi, Ver and HP1a, suggesting that the peo-dependent telomere fusion phenotype is not due to loss of terminin from chromosome ends. peo mutants are also defective in DNA replication and PCNA recruitment. However, our results suggest that general defects in DNA replication are unable to induce TFs in Drosophila cells. We thus hypothesize that DNA replication in Peo-depleted cells results in specific fusigenic lesions concentrated in heterochromatin-associated telomeres. Alternatively, it is possible that Peo plays a dual function being independently required for DNA replication and telomere capping. Telomeres are specialized structures that protect chromosome ends from incomplete replication, degradation and end-to-end fusion. Abnormalities in telomere structure or maintenance can promote a variety of human diseases including premature aging and cancer. Although all human telomeres contain the same DNA sequences, they differ from each other in the subtelomeric regions or subtelomeres. Recent work has shown that human subtelomeres control telomere replication and that abnormalities in these structures can lead to localized chromosome instability and disease. However, the relationships between subtelomeres and telomeres are currently poorly understood. Here, we have addressed this problem using the fruit fly Drosophila melanogaster as model system. Drosophila subtelomers are very different from each other as they contain different types of chromatin. We have found that mutations in a gene we called pendolino (peo) cause telomeric fusions (TFs) and that these fusions preferentially involve the telomeres associated with a tightly packed form of chromatin called heterochromatin. Interestingly, none of the 10 mutants with TFs so far described in Drosophila shows the pattern of TFs observed in peo mutants. Thus, our data provide the first demonstration that subtelomeres can affect telomere fusion. We believe that these results will stimulate further studies on the role of subtelomeres in the maintenance of genome stability.
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影响因子：
10.5
作者：
Cenci, G;Rawson, RB;Gatti, M
通讯作者：
Gatti, M
影响因子：
2
作者：
Cottee, Pauline A.;El-Osta, Youssef G. Abs;Gasser, Robin B.
通讯作者：
Gasser, Robin B.
DOI：
10.1073/pnas.94.15.8052
发表时间：
1997-07-22
影响因子：
11.1
作者：
Dimitri, P;Arca, B;Mei, E
通讯作者：
Mei, E
影响因子：
14.9
作者：
Biegert A;Mayer C;Remmert M;Söding J;Lupas AN
通讯作者：
Lupas AN
DOI：
10.1093/bioinformatics/btq662
发表时间：
2011-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Benkert P;Biasini M;Schwede T
通讯作者：
Schwede T