The RBBP6/ZBTB38/MCM10 Axis Regulates DNA Replication and Common Fragile Site Stability
Benoit Miotto,
Moredreck Chibi,
Ping Xie,
Stéphane Koundrioukoff,
Hanlie Moolman-Smook,
David Pugh,
Michelle Debatisse,
Fuchu He,
Lingqiang Zhang,
Pierre-Antoine Defossez
Affiliations
Benoit Miotto
Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France
Moredreck Chibi
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
Ping Xie
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province 116044, China
Stéphane Koundrioukoff
Institut Curie, Centre de Recherche, and Sorbonne Universités, UPMC Université Paris 06, CNRS UMR, 324426 Rue d’Ulm, 75248 Paris, France
Hanlie Moolman-Smook
US/MRC Centre for Molecular and Cellular Biology, Department of Biomedical Sciences, University of Stellenbosch Health Sciences Faculty, Tygerberg 7600, Republic of South Africa
David Pugh
Department of Biotechnology, University of the Western Cape, Bellville 7535, Republic of South Africa
Michelle Debatisse
Institut Curie, Centre de Recherche, and Sorbonne Universités, UPMC Université Paris 06, CNRS UMR, 324426 Rue d’Ulm, 75248 Paris, France
Fuchu He
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China
Lingqiang Zhang
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning Province 116044, China; Corresponding author
Pierre-Antoine Defossez
Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France; Corresponding author
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.
