Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain.
Cell Rep. 2020 Aug 4;32(5):107983. doi: 10.1016/j.celrep.2020.107983.
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.
Tousled 样激酶 1 和 2（TLK1/2）通过 ASF1 组蛋白伴侣控制组蛋白沉积，并影响细胞周期进程和基因组维护，但 TLK 介导的基因组稳定性的机制仍不确定。在这里，我们表明 TLK 缺失导致严重的染色质解压缩和基因组可及性改变，特别是影响异染色质区域。无法维持异染色质会增加重复元件的假转录，并诱导端粒的替代伸长（ALT）的特征。TLK 耗竭最终导致 cGAS-STING-TBK1 介导的先天免疫反应，该反应独立于复制应激信号，并且可以通过耗尽产生端粒外 DNA 所需的因素来减弱。对人类癌症的分析表明，在许多队列中，染色体不稳定性与高 TLK2 和低 STING 水平相关。基于这些发现，我们提出高 TLK 水平有助于染色体不稳定和 ALT+癌症的免疫逃逸。
