ATRX is a regulator of therapy induced senescence in human cells

Marta Kovatcheva,Andrew Koff,Nicolas Robine,Samuel Singer,Mark A Dickson,Aimee M Crago,Mary E Klein,Heather Geiger,William D Tap,Will Liao

doi:10.1038/s41467-017-00540-5

Marta Kovatcheva, Andrew Koff + Show 8 more

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https://doi.org/10.1038/s41467-017-00540-5

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Senescence is a state of stable cell cycle exit with important implications for development and disease. Here, we demonstrate that the chromatin remodeling enzyme ATRX is required for therapy-induced senescence. ATRX accumulates in nuclear foci and is required for therapy-induced senescence in multiple types of transformed cells exposed to either DNA damaging agents or CDK4 inhibitors. Mobilization into foci depends on the ability of ATRX to interact with H3K9me3 histone and HP1. Foci form soon after cells exit the cell cycle, before other hallmarks of senescence appear. Eliminating ATRX in senescent cells destabilizes the senescence-associated heterochromatic foci. Additionally, ATRX binds to and suppresses expression from the HRAS locus; repression of HRAS is sufficient to promote the transition of quiescent cells into senescence and preventing repression blocks progression into senescence. Thus ATRX is a critical regulator of therapy-induced senescence and acts in multiple ways to drive cells into this state.

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Senescence is a state of stable cell cycle exit with important implications for development and disease
It did affect the accumulation of SA-β-gal-positive cells (Fig. 1d), senescenceassociated heterochromatic foci (SAHF)-positive cells (Fig. 1e), the accumulation of three of the four mRNAs (CXCL1, GM-CSF, IL-6, and IL-8) that increase as part of the senescence-associated secretory phenotype (SASP) in LS8817 cells (Fig. 1f and see Methods section), and the ability of the cells to return to the cell cycle following drug removal and replating (Fig. 1g)
Given that the increase in ATRX foci first occurs within two days after CDK4 inhibitors (CDK4i) was added to these cells, and HRAS was bound and repressed at later times, once the number of foci increased to its maximum, we suggest that the gene expression program(s) regulated by ATRX during senescence were dynamically evolving

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Introduction

Senescence is a state of stable cell cycle exit with important implications for development and disease. Regardless of the mode of induction, two key features of all senescent cells are that they elaborate a cytokine expression program leading to inflammation (SASP) and there is an increase in facultative heterochromatin known as the senescenceassociated heterochromatic foci (SAHF) These conspire to prevent the cells from returning to the cell cycle once the inducing signal is removed. Senescent cells are identified by a number of associated hallmarks including failure to replicate DNA, elaboration of the SASP, accumulation of SAHF (defined as an increase in focal localization of the HP1 family of proteins) and the accumulation of senescence-associated β-galactosidase (SA-β-gal) activity Most importantly, these cells are unable to return to cell cycle once the inducer has been removed. SAHF are identified by focal chromatin deposition of Rb, the histone variant macroH2A (mH2A), the HP1 family of proteins, the high mobility group proteins (HMGA), the accumulation of proteolytically processed histone H3.3, and the accumulation of H3K9me[3] histone[18, 21, 22, 25,26,27,28]

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