Opposing roles for DNA replication initiator proteins ORC1 and CDC6 in control of Cyclin E gene transcription

  1. Manzar Hossain
  2. Bruce Stillman  Is a corresponding author
  1. 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

The following previously published data sets were used
    1. Dellino GI
    2. Cittaro D
    3. Piccioni R
    4. Luzi L
    5. Banfi S
    6. Segalla S
    7. Cesaroni M
    8. Giacca M
    9. Pelicci PG
    (2013) ORC1 ChIP
    Publicly available at the NCBI Gene Expression Omnibus (accession no. GSE37583).

Article and author information

Author details

  1. Manzar Hossain

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3399-581X
  2. Bruce Stillman

    Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    For correspondence
    stillman@cshl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9453-4091

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.

Reviewing Editor

  1. Michael R Botchan, University of California, Berkeley, United States

Publication history

  1. Received: November 2, 2015
  2. Accepted: July 18, 2016
  3. Accepted Manuscript published: July 26, 2016 (version 1)
  4. Version of Record published: August 16, 2016 (version 2)

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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  1. Manzar Hossain
  2. Bruce Stillman
(2016)
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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