Andrea Piunti

PRC1 and PRC2 regulate several cellular functions among which the ability to promote proliferation is a main feature that links Polycomb (PcG) activity to cancer development. PcGs are involved in silencing the tumour suppressor locus Ink4a-Arf whose products positively regulate pRb and p53 functions. Enhanced PcGs activity is a frequent feature of human tumours and PcGs inhibition has been proposed as a strategy for cancer treatment. However, the recurrent inactivation of pRB/p53 responses in human cancers opens a question regarding the ability of PcG proteins to control cellular proliferation independently from the Ink4a/Arf-pRb-p53 axis. Here we demonstrate that PRC1 and PRC2 control cellular proliferation and tumor development independently of the Ink4a-Arf, pRb and p53 pathways. We provide evidences that the PRCs regulate DNA replication and show that PcG loss of function induces severe defects in replication fork progression and symmetry. Collectively, these data demonstrate that PRC1 and PRC2 can act independently of major cell cycle restriction checkpoints and identify DNA replication as a novel activity by which PcGs can regulate cell proliferation and tumor development.