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Nat Commun. 2014 Apr 14;5:3649. doi: 10.1038/ncomms4649.

Polycomb proteins control proliferation and transformation independently of cell cycle checkpoints by regulating DNA replication.

Author information

1
European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy.
2
IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
3
1] Biotech Research and Innovation, University of Copenhagen, Copenhagen DK-2200, Denmark [2] Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark.
4
1] European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy [2] Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia (IIT), Milan 20139, Italy.
5
1] European Institute of Oncology, Department of Experimental Oncology, Milan 20139, Italy [2] IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy.
6
Developmental Genetics Group, RIKEN Research Center for Allergy & Immunology (RCAI), 1-7-22 Suehiuro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
7
1] Biotech Research and Innovation, University of Copenhagen, Copenhagen DK-2200, Denmark [2] Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark [3] The Danish Stem Cell Centre, University of Copenhagen, Copenhagen DK-2200, Denmark.
8
1] IFOM Foundation-FIRC Institute of Molecular Oncology Foundation, Milan 20139, Italy [2] Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, Pavia 27100, Italy.

Abstract

The ability of PRC1 and PRC2 to promote proliferation is a main feature that links polycomb (PcG) activity to cancer. PcGs silence the expression of the tumour suppressor locus Ink4a/Arf, whose products positively regulate pRb and p53 functions. Enhanced PcG activity is a frequent feature of human tumours, and PcG inhibition has been proposed as a strategy for cancer treatment. However, the recurrent inactivation of pRb/p53 responses in human cancers raises a question regarding the ability of PcG proteins to affect cellular proliferation independently from this checkpoint. Here we demonstrate that PRCs regulate cellular proliferation and transformation independently of the Ink4a/Arf-pRb-p53 pathway. We provide evidence that PRCs localize at replication forks, and that loss of their function directly affects the progression and symmetry of DNA replication forks. Thus, we have identified a novel activity by which PcGs can regulate cell proliferation independently of major cell cycle restriction checkpoints.

PMID:
24728135
PMCID:
PMC3996544
DOI:
10.1038/ncomms4649
[Indexed for MEDLINE]
Free PMC Article

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