Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France.
Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France; Department of Biotechnology, University of the Western Cape, Bellville 7535, Republic of South Africa.
Cell Rep. 2014 Apr 24;7(2):575-587. doi: 10.1016/j.celrep.2014.03.030. Epub 2014 Apr 13.
Faithful DNA replication is essential for the maintenance of genome integrity. Incomplete genome replication leads to DNA breaks and chromosomal rearrangements, which are causal factors in cancer and other human diseases. Despite their importance, the molecular mechanisms that control human genome stability are incompletely understood. Here, we report a pathway that is required for human genome replication and stability. This pathway has three components: an E3 ubiquitin ligase, a transcriptional repressor, and a replication protein. The E3 ubiquitin ligase RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38. This repressor negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Cells lacking RBBP6 experience reduced replication fork progression and increased damage at common fragile sites due to ZBTB38 accumulation and MCM10 downregulation. Our results uncover a pathway that ensures genome-wide DNA replication and chromosomal stability.
忠实的 DNA 复制对于维持基因组完整性至关重要。不完全的基因组复制会导致 DNA 断裂和染色体重排，这些是癌症和其他人类疾病的因果因素。尽管它们很重要，但控制人类基因组稳定性的分子机制尚未完全理解。在这里，我们报告了一个需要的人类基因组复制和稳定性的途径。该途径有三个组成部分：一个 E3 泛素连接酶，一个转录抑制剂，和一个复制蛋白。E3 泛素连接酶 RBBP6 泛素化和破坏转录抑制剂 ZBTB38。这种抑制剂负调控转录和染色质上的 MCM10 复制因子的水平。缺乏 RBBP6 的细胞由于 ZBTB38 的积累和 MCM10 的下调而经历复制叉推进减少和常见脆弱位点的损伤增加。我们的结果揭示了一个确保全基因组 DNA 复制和染色体稳定性的途径。
