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Cell Rep. 2014 Apr 24;7(2):575-87. doi: 10.1016/j.celrep.2014.03.030. Epub 2014 Apr 13.

The RBBP6/ZBTB38/MCM10 axis regulates DNA replication and common fragile site stability.

Author information

1
Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France.
2
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.
3
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.
4
Institut Curie, Centre de Recherche, and Sorbonne Universités, UPMC Université Paris 06, CNRS UMR, 324426 Rue d'Ulm, 75248 Paris, France.
5
US/MRC Centre for Molecular and Cellular Biology, Department of Biomedical Sciences, University of Stellenbosch Health Sciences Faculty, Tygerberg 7600, Republic of South Africa.
6
Department of Biotechnology, University of the Western Cape, Bellville 7535, Republic of South Africa.
7
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
8
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.
9
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.

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.

PMID:
24726359
DOI:
10.1016/j.celrep.2014.03.030
[Indexed for MEDLINE]
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