ATRX is a regulator of therapy induced senescence in human cells

Marta Kovatcheva, Will Liao, Mary E. Klein, Nicolas Robine, Heather Geiger, Aimee M. Crago, Mark A. Dickson, William D. Tap, Samuel Singer and Andrew Koff ()
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Marta Kovatcheva: Memorial Sloan Kettering Cancer Center
Will Liao: The New York Genome Center
Mary E. Klein: Memorial Sloan Kettering Cancer Center
Nicolas Robine: The New York Genome Center
Heather Geiger: The New York Genome Center
Aimee M. Crago: Memorial Sloan Kettering Cancer Center
Mark A. Dickson: Cornell University
William D. Tap: Cornell University
Samuel Singer: Memorial Sloan Kettering Cancer Center
Andrew Koff: Memorial Sloan Kettering Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00540-5

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