A chromatin-independent role of polycomb-like 1 to stabilize p53 and promote cellular quiescence

Gerard L. Brien, Evan Healy, Emilia Jerman, Eric Conway, Elisa Fadda, Darragh O’Donovan, Andrei V. Krivtsov, Alan M. Rice, Conor J. Kearney, Andrew Flaus, Simon S. McDade, Seamus J. Martin, Aoife McLysaght, David J. O’Connell, Scott A. Armstrong, Adrian P. Bracken

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Polycomb-like proteins 1-3 (PCL1-3) are substoichiometric components of the Polycomb-repressive complex 2 (PRC2) that are essential for association of the complex with chromatin. However, it remains unclear why three proteins with such apparent functional redundancy exist in mammals. Here we characterize their divergent roles in both positively and negatively regulating cellular proliferation. We show that while PCL2 and PCL3 are E2F-regulated genes expressed in proliferating cells, PCL1 is a p53 target gene predominantly expressed in quiescent cells. Ectopic expression of any PCL protein recruits PRC2 to repress the INK4A gene; however, only PCL2 and PCL3 confer an INK4A-dependent proliferative advantage. Remarkably, PCL1 has evolved a PRC2-and chromatin-independent function to negatively regulate proliferation. We show that PCL1 binds to and stabilizes p53 to induce cellular quiescence. Moreover, depletion of PCL1 phenocopies the defects in maintaining cellular quiescence associated with p53 loss. This newly evolved function is achieved by the binding of the PCL1 N-terminal PHD domain to the C-terminal domain of p53 through two unique serine residues, which were acquired during recent vertebrate evolution. This study illustrates the functional bifurcation of PCL proteins, which act in both a chromatin-dependent and a chromatin-independent manner to regulate the INK4A and p53 pathways.

Original languageEnglish
Pages (from-to)2231-2243
Number of pages13
JournalGenes and Development
Volume29
Issue number21
Early online date22 Oct 2015
DOIs
Publication statusPublished - 1 Nov 2015

Keywords

  • Cellular quiescence
  • Cellular senescence
  • Neofunctionalization
  • P53
  • PHD reader domain
  • Polycomb-like

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Brien, G. L., Healy, E., Jerman, E., Conway, E., Fadda, E., O’Donovan, D., ... Bracken, A. P. (2015). A chromatin-independent role of polycomb-like 1 to stabilize p53 and promote cellular quiescence. Genes and Development, 29(21), 2231-2243. https://doi.org/10.1101/gad.267930.115