title: The RBBP6/ZBTB38/MCM10 axis regulates DNA replication and common fragile site stability.
abstract: 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.
authors.affiliation: Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Miotto
authors.affiliation: 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.
authors.forename: Moredreck
authors.initials: M
authors.lastname: Chibi
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Xie
authors.affiliation: Institut Curie, Centre de Recherche, and Sorbonne Universités, UPMC Université Paris 06, CNRS UMR, 324426 Rue d'Ulm, 75248 Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Koundrioukoff
authors.affiliation: US/MRC Centre for Molecular and Cellular Biology, Department of Biomedical Sciences, University of Stellenbosch Health Sciences Faculty, Tygerberg 7600, Republic of South Africa.
authors.forename: Hanlie
authors.initials: H
authors.lastname: Moolman-Smook
authors.affiliation: Department of Biotechnology, University of the Western Cape, Bellville 7535, Republic of South Africa.
authors.forename: David
authors.initials: D
authors.lastname: Pugh
authors.affiliation: Institut Curie, Centre de Recherche, and Sorbonne Universités, UPMC Université Paris 06, CNRS UMR, 324426 Rue d'Ulm, 75248 Paris, France.
authors.forename: Michelle
authors.initials: M
authors.lastname: Debatisse
authors.affiliation: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
authors.forename: Fuchu
authors.initials: F
authors.lastname: He
authors.affiliation: 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. Electronic address: zhanglq@nic.bmi.ac.cn.
authors.forename: Lingqiang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France. Electronic address: pierre-antoine.defossez@univ-paris-diderot.fr.
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Defossez
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D064110:Minichromosome Maintenance Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C489613:MCM10 protein, human; D012097:Repressor Proteins; C508975:ZBTB38 protein, human; C098584:RBBP6 protein, human; D044767:Ubiquitin-Protein Ligases; D064110:Minichromosome Maintenance Proteins