Interplay Between Homeobox Proteins and Polycomb Repressive Complexes in P16INK⁴a Regulation

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2013 Mar 5

PMID 23455154

Citations 26

Authors

Nadine Martin

Nikolay Popov

Francesca Aguilo

Ana OLoghlen

Selina Raguz

Ambrosius P Snijders

Gopuraja Dharmalingam

Side Li

Efstathia Thymiakou

Thomas Carroll

Bernd B Zeisig

Chi Wai Eric So

Gordon Peters

Vasso Episkopou

Martin J Walsh

Jesus Gil

Affiliations

Soon will be listed here.

Abstract

The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16(INK4a) as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16(INK4a) transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16(INK4a). Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16(INK4a). Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16(INK4a). Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer.

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