The RBBP6/ZBTB38/MCM10 Axis Regulates DNA Replication and Common Fragile Site Stability

Abstract

Summary: 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. : DNA replication duplicates the genome at every cell cycle. Miotto et al. have now identified a molecular pathway that ensures proper replication of the mammalian genome. Common fragile sites are regions in the mammalian genome that are prone to loss when DNA replication is suboptimal. The new data show that common fragile sites are exquisitely sensitive to the activity of this RBBP6/ZBTB38/MCM10 axis, suggesting that deregulation of these factors may underlie genome instability and human disease.