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ATRX loss induces telomere dysfunction and necessitates induction of alternative lengthening of telomeres during human cell immortalization
Author(s) -
Li Fei,
Deng Zhong,
Zhang Ling,
Wu Caizhi,
Jin Ying,
Hwang Inah,
Vladimirova Olga,
Xu Libo,
Yang Lynnie,
Lu Bin,
Dheekollu Javaraju,
Li JianYi,
Feng Hua,
Hu Jian,
Vakoc Christopher R,
Ying Haoqiang,
Paik Jihye,
Lieberman Paul M,
Zheng Hongwu
Publication year - 2019
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201796659
Subject(s) - atrx , death associated protein 6 , telomere , biology , telomerase , histone , microbiology and biotechnology , dna repair , chromatin , genetics , dna , nuclear protein , mutation , gene , transcription factor
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.