Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres
Sandra Segura-Bayona,
Marina Villamor-Payà,
Camille Stephan-Otto Attolini,
Lars M. Koenig,
Maria Sanchiz-Calvo,
Simon J. Boulton,
Travis H. Stracker
Affiliations
Sandra Segura-Bayona
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; Corresponding author
Marina Villamor-Payà
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain
Camille Stephan-Otto Attolini
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain
Lars M. Koenig
Division of Clinical Pharmacology, University Hospital, LMU Munich, 80337 Munich, Germany
Maria Sanchiz-Calvo
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain
Simon J. Boulton
The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Travis H. Stracker
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain; Corresponding author
Summary: 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.
