1 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet2 Administration, BRIC Administration, BRIC, Københavns Universitet3 The Danish Stem Cell Center, Faculty of Health and Medical Sciences, Københavns Universitet4 European Institute of Oncology, Department of Experimental Oncology5 IFOM Foundation-FIRC Institute of Molecular Oncology Foundation6 Helin Group, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet7 Developmental Genetics Group, RIKEN Research Center for Allergy & Immunology (RCAI), 1-7-22 Suehiuro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.8 BRIC Administration, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet9 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet10 Helin Group, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet11 BRIC Administration, BRIC, Faculty of Health and Medical Sciences, Københavns Universitet
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.