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Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131023 | GEO | 2020/07/21

REPOSITORIES: GEO

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Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [ChIP-Seq]

Project description:The Tousled like kinases 1 and 2 (TLK1/2) control histone deposition through the ASF1 histone chaperones and are regulated by the DNA damage response. Depletion of TLK activity caused replication stress, increased chromosomal instability and cell arrest or death. Here, we show that stalled forks in TLK depleted cells are processed by BLM, SAMHD1 and the MRE11 nuclease to generate ssDNA and activate checkpoint signaling. TLK depletion also impaired heterochromatin maintenance, inducing features of alternative lengthening of telomeres and increasing spurious expression of other repetitive elements, associated with impaired deposition of the histone variant H3.3. TLK depletion culminated in a BLM-dependent, STING-mediated innate immune response. In many human cancers, TLK1/2 expression correlated with signatures of chromosomal instability and anti-correlated with STING and innate and adaptive immune response signatures. Together, our results show that TLK activity protects replication forks from active processing, contributes to chromatin silencing and suppresses innate immune responses, suggesting that TLK amplification may protect chromosomally unstable cancers from immune detection.

2020-07-21 | GSE131021 | GEO

Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [RNA-Seq]

2020-07-21 | GSE131019 | GEO

Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [HeLa ATAC-Seq]

2020-07-21 | GSE131022 | GEO

Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [U2OS ATAC-Seq]

2020-07-21 | GSE131020 | GEO

Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling

Project description:Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling

| PRJNA542332 | ENA

Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [RNA-Seq]

Project description:Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [RNA-Seq]

| PRJNA542336 | ENA

Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [ChIP-Seq]

Project description:Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [ChIP-Seq]

| PRJNA542334 | ENA

Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [HeLa ATAC-Seq]

Project description:Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [HeLa ATAC-Seq]

| PRJNA542333 | ENA

Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [U2OS ATAC-Seq]

Project description:Tousled-like kinase activity is required for transcriptional silencing and suppression of innate immune signaling [U2OS ATAC-Seq]

| PRJNA542335 | ENA

Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres.

Project description: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.

| S-EPMC7408502 | biostudies-literature

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