酵母泛素连接酶Bre1及其介导的H2B泛素化修饰在DNA双链断裂修复中的作用与机制研究

DNA double-strand breaks (DSBs) pose a serious threat to genome stability, and are closely related to human cancers. It has been shown that histone H2B ubiquitination plays an important role in repair of DSB in human cells. However, whether this modification is required for DSB repair in the model species Saccharomyces cerevisiae remains unknown. Therefore, we investigated the role of Bre1, the E3 ligase for H2B-K123 ubiquitination, in DSB repair. We found that: 1) Bre1 plays an indispensable role in response to DNA damaging-agents; 2) Bre1 is essential for proper activation of the DNA damage checkpoint; 3) Bre1 promotes DSB repair by both homologous recombination and non-homologous end joining, and 4) Bre1 acts through controlling the ubiquitination of H2B. In this study, we will employ yeast as a model to investigate the role of Bre1 and H2B ubiquitination in DSB repair. Our goal is to fully elucidate its function and the underlying mechanism. In addition, we aim to address the potential crosstalk between H2B ubiquitination and H3-H4 acetylation in DSB repair. Given that DNA repair is evolutionarily conserved, our study could provide insights into the molecular details on how the dynamic histone modifications may influence DSB repair and genome stability in eukaryotes including in human.

DNA双链断裂(DSB)对基因组稳定性构成严重威胁，与人类癌症密切关联。在人类细胞中，组蛋白H2B泛素化修饰调控DSB修复，但该修饰在模式生物酵母的DSB修复和基因组稳定性中的功能未知。鉴于此，我们前期研究了酵母H2B泛素化E3连接酶Bre1在DSB修复中的功能，发现：1)Bre1在应对致DNA损伤药物的抗性中起重要作用；2)Bre1促进DSB引起的检查点激活；3)Bre1促进同源重组和非同源末端连接两条修复途径；4)Bre1通过H2B泛素化来调控DSB修复。本课题以酵母为材料，研究Bre1及H2B泛素化在DSB修复中的作用，以期全面揭示其功能及作用机制；同时，也将研究并阐明H2B泛素化与组蛋白H3-H4乙酰化修饰在DSB修复中的功能关联。鉴于DNA修复机制的保守性，本研究将有利于深入理解真核生物包括人类中组蛋白修饰如何调控DNA修复和基因组稳定性。

DNA双链断裂(DSB)对基因组稳定性构成严重威胁，与人类癌症密切关联。在人类细胞中，组蛋白H2B泛素化修饰调控DSB修复，但该修饰在模式生物酵母的DSB修复和基因组稳定性中的功能未知。鉴于此，我们前期研究了酵母H2B泛素化E3连接酶Bre1在DSB修复中的功能，发现：1)Bre1在应对致DNA损伤药物的抗性中起重要作用；2)Bre1促进DSB引起的检查点激活；3)Bre1促进同源重组和非同源末端连接两条修复途径；4)Bre1通过H2B泛素化来调控DSB修复。本课题以酵母为材料，研究Bre1及H2B泛素化在DSB修复中的作用，以期全面揭示其功能及作用机制；同时，也将研究并阐明H2B泛素化与组蛋白H3-H4乙酰化修饰在DSB修复中的功能关联。鉴于DNA修复机制的保守性，本研究将有利于深入理解真核生物包括人类中组蛋白修饰如何调控DNA修复和基因组稳定性。