Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription
- Cold Spring Harbor Laboratory, United States
Abstract
Newly-born cells either continue to proliferate or exit the cell division cycle. This decision involves delaying expression of Cyclin E that promotes DNA replication. ORC1, the Origin Recognition Complex (ORC) large subunit, is inherited into newly-born cells after it binds to condensing chromosomes during the preceding mitosis. We demonstrate that ORC1 represses Cyclin E gene (CCNE1) transcription, an E2F1 activated gene that is also repressed by the Retinoblastoma (RB) protein. ORC1 binds to RB, the histone methyltransferase SUV39H1 and to its repressive histone H3K9me3 mark. ORC1 cooperates with SUV39H1 and RB protein to repress E2F1-dependent CCNE1 transcription. In contrast, the ORC1-related replication protein CDC6 binds Cyclin E-CDK2 kinase and in a feedback loop removes RB from ORC1, thereby hyper-activating CCNE1 transcription. The opposing effects of ORC1 and CDC6 in controlling the level of Cyclin E ensures genome stability and a mechanism for linking directly DNA replication and cell division commitment.
Data availability
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ORC1 ChIPPublicly available at the NCBI Gene Expression Omnibus (accession no. GSE37583).
Article and author information
Author details
Funding
National Cancer Institute (CA13106)
- Bruce Stillman
National Cancer Institute (CA45508)
- Bruce Stillman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Hossain & Stillman
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription
eLife 5:e12785.
https://doi.org/10.7554/eLife.12785
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