Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors

Lee, Sung Bau; Segura-Bayona, Sandra; Villamor-Payà, Marina; Saredi, Giulia; Todd, Matthew A. M.; Attolini, Camille Stephan‐Otto; Chang, Ting; Stracker, Travis H.; Groth, Anja

doi:10.1126/sciadv.aat4985

Cited by 50 publications

(78 citation statements)

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“…Unscheduled S-phase entry may generate an environment where nucleotides, replication factors, histones or other resources are limiting (Bester et al, 2011;Halazonetis et al, 2008;Lee et al, 2018b). In addition, oncogene overexpression can induce the firing of replication origins within highly transcribed genes, leading to replication-transcription conflicts that can provoke chromosomal rearrangements (Kotsantis et al, 2018;Macheret and Halazonetis, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…In cancer cells, defective chromatin assembly caused by depletion of ASF1B limits cellular proliferation and high levels of ASF1B correlate with poor patient outcome in breast cancer (Corpet et al, 2011). Similarly, Tousled like kinases (TLKs) are critical for nucleosome assembly during DNA synthesis and for replication fork stability, but in contrast to ASF1 depletion that arrests forks without provoking ssDNA accumulation, their loss leads to acute replication stress, characterized by increased levels of ssDNA and DNA double-strand breaks (DSBs) (Groth et al, 2007;Lee et al, 2018b;Mejlvang et al, 2014). Both TLK1 and TLK2 are maintained in most cancers and often amplified.…”

Section: Introductionmentioning

confidence: 99%

“…Both TLK1 and TLK2 are maintained in most cancers and often amplified. In some cases their increased expression correlates with poor prognosis, suggesting that they may be potential cancer targets (Kim et al, 2016;Lee et al, 2018b).…”

Section: Introductionmentioning

confidence: 99%

“…As our previous results indicated that the depletion of TLKs caused replication stress, chromosomal instability and cell arrest or death (Lee et al, 2018b), we sought to better understand the origin of these phenotypes and the mechanisms leading to toxicity in TLK depleted cells. Here, we show that replication stress signaling following the depletion of TLKs is dependent on BLM, SAMHD1 and MRE11 nuclease activity and often occurs in the proximity of telomeres, natural sites of replication stress (Sfeir et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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

Segura-Bayona

Villamor-Payà

Attolini

et al. 2019

Preprint

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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 BLMdependent, 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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Segura-Bayona

Villamor-Payà

Attolini

et al. 2019

Preprint

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“…High-throughput microscopy (HTM)-mediated quantification of the nuclear intensity of SNAP-H3.1/3 was performed as described (Lee et al, 2018). Forty-eight images per well were automatically acquired with a robotized fluorescence microscopy station (ScanR, Olympus) at 40´ magnification.…”

Section: Snap-based Experimentsmentioning

confidence: 99%

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

Serra-Bardenys¹,

Tian²,

Querol³

et al. 2020

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The histone modification of H3 oxidized at lysine 4 (H3K4ox) is catalyzed by lysyl oxidase-like 2 (LOXL2) and is enriched in heterochromatin in triple-negative breast cancer (TNBC) cells. Although H3K4ox has been linked to the maintenance of compacted chromatin, the molecular mechanism underlying this maintenance is unknown. Here we show that H3K4ox is read by the CRL4B complex, leading to the ubiquitination of histone H2A through the E3 ligase RBX1. Finally, interactions between RUVBL1/2 and LOXL2 are involved in the incorporation of the histone variant H2A.Z, which plays an essential role in the mechanism controlling the dynamics of oxidized H3. Maintenance of H3K4ox in chromatin is essential for heterochromatin properties, and disruption of any of the members involved in this pathway blocks the oncogenic properties of TNBC cells. 2018). H3K9me2/3 are recognized by heterochromatin protein 1 (HP1), which has a major role in ensuring heterochromatin compaction, spreading, and inheritance (Bannister et al., 2001).Heterochromatin is not only essential for the maintenance of genome stability but can also directly affect genome integrity, through changes in its highly dynamic structure (Janssen et al., 2018).Therefore, there is a pressing need to improve our understanding of the role of heterochromatin, and the mechanisms by which it is maintained at a mechanistic level. To address this, we employed, unbiased proteomic assays to identify LOXL2 partners, as well as H3K4ox readers. We found that LOXL2 interacts with members of the SRCAP and TIP60 complexes, and that H3K4ox is read by the CRL4B complex. Both of these complexes are involved in loading the histone H2A variant, H2A.Z, into chromatin (Buschbeck and Hake, 2017; Morrison and Shen, 2009). We also discovered that the CRL4B complex is involved in the ubiquitination of H2A by RBX1, that is required for the exchange of the H2A variant, H2A.Z. Notably, both in vitro and in vivo, these series of events are necessary to maintain condensed chromatin in triple-negative breast cancer (TNBC) cells. Knocking down any component of this pathway resulted in inhibition of oncogenic and metastatic traits in TNBC cells, including proliferation, migration, invasion, and in vivo tumor formation capacity. Thus, we propose the existence of a direct link between oxidation of H3, chromatin condensation, and tumorigenic capacities, and argue that any of the components described in the H3K4ox pathway could potentially be targetable factors for treating TNBC. RESULTS The Roles of LOXL2, RUVBL2, and H2A.Z in Chromatin CondensationWe revisited a tandem-affinity purification approach previously published by our lab to identify putative LOXL2 interactors that might be involved in the maintenance or generation of compacted chromatin induced by H3K4ox-LOXL2 (Cebria-Costa et al., 2019;Herranz et al., 2016). Analysis of the new list of interactors showed the presence of two AAA+ ATPases (RUVBL1 and RUVBL2), DMAP1 and BAF53, all of which are members of the SRCAP and TIP60 complexes ( Figure 1A a...

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Expanded Potential Stem Cells from Human Embryos Have an Open Chromatin Configuration with Enhanced Trophoblast Differentiation Ability

et al. 2023

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Human expanded potential stem cells (hEPSC) have been derived from human embryonic stem cells and induced pluripotent stem cells. Here direct derivation of hEPSC from human pre-implantation embryos is reported. Like the reported hEPSC, the embryo-derived hEPSC (hEPSC-em) exhibit a transcriptome similar to morula, comparable differentiation potency, and high genome editing efficiency. Interestingly, the hEPSC-em show a unique H3 lysine-4 trimethylation (H3K4me3) open chromatin conformation; they possess a higher proportion of H3K4me3 bound broad domain (>5 kb) than the reported hEPSC, naive, and primed embryonic stem cells. The open conformation is associated with enhanced trophoblast differentiation potency with increased trophoblast gene expression upon induction of differentiation and success in derivation of trophoblast stem cells with bona fide characteristics. Hippo signaling is specifically enriched in the H3K4me3 broad domains of the hEPSC-. Knockout of the Hippo signaling gene, YAP1 abolishes the ability of the embryo-derived EPSC to form trophoblast stem cells.

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Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors

Abstract: TLKs promote nucleosome assembly and prevent fork collapse and DNA damage upon checkpoint or PARP inhibition.

Cited by 50 publications

References 47 publications

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

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

Maintaining oxidized H3 in heterochromatin is required for the oncogenic capacity of triple-negative breast cancer cells

Expanded Potential Stem Cells from Human Embryos Have an Open Chromatin Configuration with Enhanced Trophoblast Differentiation Ability

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