Tousled-like kinases (TLKs) are a family of highly conserved serine/threonine protein kinases and are a potential therapeutic target for cancer treatment due to their central role in DNA repair and replication. Researchers from the Genomic Instability and Cancer Laboratory at the Institute for Research (IRB) in Biomedicine in Barcelona, have found that TLK inhibition triggers the innate immune system.

Their findings were published in Cell Reports in a paper titled, “Tousled-like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres.”

The innate immune system includes physical and anatomical barriers as well as effector cells, antimicrobial peptides, soluble mediators, and cell receptors.

Study leader Travis H. Stracker, PhD, and leader at the National Cancer Institute at the NIH stated, “We believe the TLKs are promising targets for cancer therapy and want to understand more about how they work and how cells respond to their reduction or loss.”

“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),” wrote the authors.

The researchers observed that blocking TLKs triggers the ALT pathway, which is used by many cancers to maintain telomeres and allow cells to continue dividing. While most cancers rely on reactivation of telomerase, a significant fraction utilizes the recombination ALT pathway. ALT is enriched in tumors of mesenchymal origin, including those arising from bone, soft tissue, and the nervous system.

The researchers found that the activation of the ALT pathway triggers the innate immune system, potentially attracting immune cells, such as macrophages and T lymphocytes.

“The activation of innate immunity in cancer has recently become an active area of research as it has become clear that the innate immune response influences chemotherapy and immunotherapy,” explained Stracker.

Not all regions in DNA have the same function. Some regions are called heterochromatin, that have a regulatory and structural function, but do not contain genes that give rise to proteins. Failure to maintain heterochromatin increases spurious transcription of repetitive elements and induces features of ALT.

Researchers also observed another effect due to TLK inhibition. The heterochromatin, which is usually compacted, ceases to be so, thereby becoming more accessible to the RNA production machinery and leading to an altered composition in the cell.

“This could help us understand our previous observation that TLK depletion caused replication stress and help us exploit the effects of TLK depletion for cancer therapy,” said Sandra Segura-Bayona, current postdoctoral fellow in the laboratory headed by Simon Boulton at the Francis Crick Institute in London.

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