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

EMBO J. 2019 Oct 1;38(19):e96659. doi: 10.15252/embj.201796659. Epub 2019 Aug 27.

Abstract

Loss of the histone H3.3-specific chaperone component ATRX or its partner DAXX frequently occurs in human cancers that employ alternative lengthening of telomeres (ALT) for chromosomal end protection, yet the underlying mechanism remains unclear. Here, we report that ATRX/DAXX does not serve as an immediate repressive switch for ALT. Instead, ATRX or DAXX depletion gradually induces telomere DNA replication dysfunction that activates not only homology-directed DNA repair responses but also cell cycle checkpoint control. Mechanistically, we demonstrate that this process is contingent on ATRX/DAXX histone chaperone function, independently of telomere length. Combined ATAC-seq and telomere chromatin immunoprecipitation studies reveal that ATRX loss provokes progressive telomere decondensation that culminates in the inception of persistent telomere replication dysfunction. We further show that endogenous telomerase activity cannot overcome telomere dysfunction induced by ATRX loss, leaving telomere repair-based ALT as the only viable mechanism for telomere maintenance during immortalization. Together, these findings implicate ALT activation as an adaptive response to ATRX/DAXX loss-induced telomere replication dysfunction.

Keywords: ALT; ATRX/DAXX; DNA damage; immortalization; telomere.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Co-Repressor Proteins / genetics*
  • DNA Repair
  • Gene Deletion
  • HEK293 Cells
  • Humans
  • Molecular Chaperones / genetics*
  • Telomerase / metabolism
  • Telomere / metabolism*
  • Telomere Homeostasis*
  • X-linked Nuclear Protein / genetics*

Substances

  • Co-Repressor Proteins
  • DAXX protein, human
  • Molecular Chaperones
  • TERT protein, human
  • Telomerase
  • ATRX protein, human
  • X-linked Nuclear Protein

Associated data

  • GEO/GSE130640