Brien, Gerard L. and Healy, Evan and Jerman, Emilia and Conway, Eric and Fadda, Elisa and O'Donovan, Darragh and Krivtsov, Andrei V. and Rice, Alan M. and Kearney, Conor J. and Flaus, Andrew and McDade, Simon S. and Martin, Seamus and McLysaght, Aiofe and O'Connell, David J. and Armstrong, Scott and Bracken, Adrian P. (2015) A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence. Genes and Development, 29. pp. 2231-2243. ISSN 1549-5477

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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.

Item Type:	Article
Keywords:	Polycomb-like; cellular senescence; p53; cellular quiescence; PHD reader domain; neofunctionalization;
Academic Unit:	Faculty of Science and Engineering > Chemistry
Item ID:	12538
Identification Number:	https://doi.org/10.1101/gad.267930.115
Depositing User:	Elisa Fadda
Date Deposited:	06 Mar 2020 17:13
Journal or Publication Title:	Genes and Development
Publisher:	Cold Spring Harbor Laboratory Press
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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