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

Andrea Piunti, Alessandra Rossi, Aurora Cerutti, Mareike Albert, Sriganesh Jammula, Andrea Scelfo, Laura Cedrone, Giulia Fragola, Linda Olsson, Haruhiko Koseki, Giuseppe Testa, Stefano Casola, Kristian Helin, Fabrizio d’Adda di Fagagna and Diego Pasini ()
Additional contact information
Andrea Piunti: European Institute of Oncology
Alessandra Rossi: European Institute of Oncology
Aurora Cerutti: IFOM Foundation—FIRC Institute of Molecular Oncology Foundation
Mareike Albert: Biotech Research and Innovation, University of Copenhagen
Sriganesh Jammula: European Institute of Oncology
Andrea Scelfo: European Institute of Oncology
Laura Cedrone: European Institute of Oncology
Giulia Fragola: European Institute of Oncology
Linda Olsson: Biotech Research and Innovation, University of Copenhagen
Haruhiko Koseki: Developmental Genetics Group, RIKEN Research Center for Allergy & Immunology (RCAI), 1-7-22 Suehiuro-cho, Tsurumi
Giuseppe Testa: European Institute of Oncology
Stefano Casola: IFOM Foundation—FIRC Institute of Molecular Oncology Foundation
Kristian Helin: Biotech Research and Innovation, University of Copenhagen
Fabrizio d’Adda di Fagagna: IFOM Foundation—FIRC Institute of Molecular Oncology Foundation
Diego Pasini: European Institute of Oncology

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4649

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