Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres
The Tousled-like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperone and influence cell cycle progression and genome maintenance, yet the mechanisms underlying TLK-mediated genome stability remain uncertain. Here, we show that TLK loss results in severe chromatin d...
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Veröffentlicht in: | Cell reports (Cambridge) 2020-08, Vol.32 (5), p.107983-107983, Article 107983 |
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Zusammenfassung: | The Tousled-like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperone and influence cell cycle progression and genome maintenance, yet the mechanisms underlying TLK-mediated genome stability remain uncertain. Here, we show that TLK loss results in severe chromatin decompaction and altered genome accessibility, particularly affecting heterochromatic regions. Failure to maintain heterochromatin increases spurious transcription of repetitive elements and induces features of alternative lengthening of telomeres (ALT). TLK depletion culminates in a cGAS-STING-TBK1-mediated innate immune response that is independent of replication-stress signaling and attenuated by the depletion of factors required to produce extra-telomeric DNA. Analysis of human cancers reveals that chromosomal instability correlates with high TLK2 and low STING levels in many cohorts. Based on these findings, we propose that high TLK levels contribute to immune evasion in chromosomally unstable and ALT+ cancers.
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•TLK-deficient cells have increased accessibility at heterochromatin regions•TLK1/2 suppress spurious transcription and telomere hyper-recombination•Extra-telomeric DNA generated upon TLK loss promotes innate immune signaling•cGAS-STING-TBK1 signaling in TLK-deficient cells is independent of replication stress
Segura-Bayona et al. find the Tousled-like kinases (TLKs) maintain chromatin at repetitive genome elements and telomeres. TLK depletion results in heterochromatin desilencing and induction of alternative lengthening of telomeres (ALT), robustly activating cGAS-STING-TBK1-mediated innate immune responses. This suggests TLKs represent a druggable vulnerability in ALT+ and chromosomally unstable tumor cells. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2020.107983 |