The Budding Yeast Ubiquitin Protease Ubp7 Is a Novel Component Involved in S Phase Progression
The Budding Yeast Ubiquitin Protease Ubp7 Is a Novel Component Involved in S Phase Progression
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DOI：
10.1074/jbc.m115.671057
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发表时间：
2016-02-26
影响因子：
4.8
通讯作者：
Bernstein, Kara A.
中科院分区：
文献类型：
--
作者：
Boehm, Stefanie;Szakal, Barnabas;Bernstein, Kara A.
DNA损伤必须以准确和及时的方式修复，以保持基因组的稳定性。防止基因组不稳定的细胞机制对人类健康至关重要，因为基因组不稳定被认为是癌症的标志。保守途径统称为DNA损伤反应，确保正确的DNA损伤识别和修复。许多DNA损伤反应组分的功能通过翻译后修饰（包括泛素化）进行微调。这不仅涉及负责将泛素缀合至底物的酶级联，而且还需要介导泛素的定向去除的酶。去泛素化酶从底物中去除泛素以防止降解或介导信号传导功能。酿酒酵母去泛素化酶Ubp7先前已被表征为内吞因子。然而，在这里，我们确定Ubp7作为一个新的因素，影响S期进展后，羟基脲治疗，并证明了进化和遗传相互作用的Ubp7与DNA损伤修复途径的同源重组和核苷酸切除修复。我们发现UBP7的缺失使细胞对羟基脲和顺铂敏感，并证明在这些条件下稳定复制叉的因素至关重要。此外，ubp7 δ细胞在通过羟基脲处理的检查点激活后表现出S期进展缺陷。Ubp7 Delta突变体对参与组蛋白维持和修饰的因子具有上位性，我们发现Ubp7的一个子集与染色质相关。总之，我们的研究结果表明，Ubp7有助于通过影响复制叉的染色质状态的S期进展，我们建议组蛋白H2B泛素化作为Ubp7的潜在底物。
DNAdamage must be repaired in an accurate and timely fashion to preserve genome stability. Cellular mechanisms preventing genome instability are crucial to human health because genome instability is considered a hallmark of cancer. Collectively referred to as the DNA damage response, conserved pathways ensure proper DNA damage recognition and repair. The function of numerous DNA damage response components is fine-tuned by posttranslational modifications, including ubiquitination. This not only involves the enzyme cascade responsible for conjugating ubiquitin to substrates but also requires enzymes that mediate directed removal of ubiquitin. Deubiquitinases remove ubiquitin from substrates to prevent degradation or to mediate signaling functions. The Saccharomyces cerevisiae deubiquitinase Ubp7 has been characterized previously as an endocytic factor. However, here we identify Ubp7 as a novel factor affecting S phase progression after hydroxyurea treatment and demonstrate an evolutionary and genetic interaction of Ubp7 with DNA damage repair pathways of homologous recombination and nucleotide excision repair. We find that deletion of UBP7 sensitizes cells to hydroxyurea and cisplatin and demonstrate that factors that stabilize replication forks are critical under these conditions. Furthermore, ubp7 Delta cells exhibit an S phase progression defect upon checkpoint activation by hydroxyurea treatment. ubp7 Delta mutants are epistatic to factors involved in histone maintenance and modification, and we find that a subset of Ubp7 is chromatin-associated. In summary, our results suggest that Ubp7 contributes to S phase progression by affecting the chromatin state at replication forks, and we propose histone H2B ubiquitination as a potential substrate of Ubp7.