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

Fei Li, Zhong Deng, Ling Zhang, Caizhi Wu, Ying Jin, Inah Hwang, Olga Vladimirova, Libo Xu, Lynnie Yang, Bin Lu, Javaraju Dheekollu, Jian Yi Li, Hua Feng, Jian Hu, Christopher R. Vakoc, Haoqiang Ying, Jihye Paik, Paul M. Lieberman, Hongwu Zheng

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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.

Original languageEnglish
Article numbere96659
JournalEMBO Journal
Volume38
Issue number19
DOIs
StatePublished - 1 Oct 2019

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Keywords

  • ALT
  • ATRX/DAXX
  • DNA damage
  • immortalization
  • telomere

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