The RBBP6/ZBTB38/MCM10 Axis Regulates DNA Replication and Common Fragile Site Stability
The RBBP6/ZBTB38/MCM10 Axis Regulates DNA Replication and Common Fragile Site Stability
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DOI：
10.1016/j.celrep.2014.03.030
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发表时间：
2014-04-01
期刊：
影响因子：
8.8
通讯作者：
Defossez, Pierre-Antoine
中科院分区：
文献类型：
--
作者：
Miotto, Benoit;Chibi, Moredreck;Defossez, Pierre-Antoine
忠实的DNA复制对于维持基因组的完整性至关重要。不完整的基因组复制导致DNA断裂和染色体重排，这是癌症和其他人类疾病的致病因素。尽管其重要性，控制人类基因组稳定性的分子机制尚未完全理解。在这里，我们报告了人类基因组复制和稳定性所需的途径。该途径有三个组成部分：E3泛素连接酶，转录抑制因子和复制蛋白。E3泛素连接酶RBBP6使转录抑制子ZBTB38泛素化并使其不稳定。该阻遏物负调节染色质上的MCM10复制因子的转录和水平。由于ZBTB38积累和MCM10下调，缺乏RBBP6的细胞经历复制叉进展减少和常见脆性位点损伤增加。我们的研究结果揭示了确保全基因组DNA复制和染色体稳定性的途径。
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.