ATRX is a regulator of therapy induced senescence in human cells

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.

ATRX loss induces telomere dysfunction and necessitates induction of alternative lengthening of telomeres during human cell immortalization

“…How can the anti‐proliferation response of ATRX or DAXX loss be reconciled with their tumor suppressor roles? It is important to point out that besides their crucial roles in telomere maintenance, ATRX and DAXX also participate in many other biological processes, including gene expression (Gibbons et al , ; Law et al , ; Ratnakumar et al , ; Sarma et al , ; Danussi et al , ), DNA damage repair (Koschmann et al , ; Juhasz et al , ), senescence (Kovatcheva et al , ), and regulation of chromatin state and composition (Law et al , ; He et al , ; Voon et al , ). We speculate that DAXX and ATRX may exert their tumor suppressor roles independently of their telomere maintenance function.…”

Mutant ATRX: uncovering a new therapeutic target for glioma

“…ATRX is required for the development of senescence in response to cytostatic chemotherapy by playing a role in the maintenance of the SAHF. This role is dependent on the capacity of ATRX to recognize H3K9me3 and HP1 [75, 76]. ATRX was also shown to interact directly with the HRAS locus, inhibiting expression of this gene.…”

“…ATRX was also shown to interact directly with the HRAS locus, inhibiting expression of this gene. Inhibition of the HRAS pathway is required for senescence [75]. These findings may indicate that loss of ATRX confers an advantage for developing cancer cells by means of repressing senescence pathways.…”

To Cycle or Fight—CDK4/6 Inhibitors at the Crossroads of Anticancer Immunity

“…One really interesting observation that may be pivotal is that in addition to blocking cell proliferation, CDK4/6 inhibitors can induce senescence-an irreversible distinct cellular state characterized by the absence of proliferation markers, expression of tumorsuppressor genes, senescence-associated beta-galactosidase activity, and the presence of senescence-associated heterochromatin foci in multiple Rb-proficient cell lines (53,54). The decision whether to transition from quiescence into senescence is the subject of much ongoing work, and the outcome appears to cell-type specific with downregulation of MDM2, redistribution of the chromatinremodeling enzyme ATRX, repressions of oncogenes as well as upregulation of proteasomal homeostasis necessary for the shift to senescence (55)(56)(57). Senescent cells secrete a collection of inflammatory cytokines, chemokines, and proteinases, collectively referred to as the senescence-associated secretory phenotype (SASP) which recruits and activates distinct cells from the innate and adaptive immune system, such as macrophages and natural killer cells as well as T cells (58,59).…”