Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicry

Simon, Bertrand; Lou, Hua; Calderwood, David A.; Shi, Guangda; Boggon, Titus J.; Turk, Benjamin E.

doi:10.1038/s41467-022-28427-0

Cited by 20 publications

(13 citation statements)

References 89 publications

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“…In order to validate the analysis results of differentially expressed genes, the expression levels of three differentially expressed genes in sperm samples of the experimental group and control group related to sperm DNA damage and repair, including PMS1, TP53BP1 and TLK2, were detected by RT-qPCR. Tousled-like kinases (TLKs) are nuclear serine-threonine kinases essential for genome stability, proper cell division and normal development in numerous organisms (Simon et al, 2022), whose activity has been linked to DNA replication, DNA repair, chromatin structure and etc. (Segura-Bayona et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Investigation of the mechanisms leading to human sperm DNA damage based on transcriptome analysis by RNA-seq techniques

Zhu¹,

Ye²,

Zhang³

et al. 2023

Reproductive BioMedicine Online

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Section: Discussionmentioning

confidence: 99%

Investigation of the mechanisms leading to human sperm DNA damage based on transcriptome analysis by RNA-seq techniques

Zhu¹,

Ye²,

Zhang³

et al. 2023

Reproductive BioMedicine Online

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“…2a, b ). Apart from the kinase activity, Tousled-Like kinase 2 also acts as an ASF1 regulator by mimicking H3 and recognizing ASF1’s H3-H4 binding pocket 43 . Although the two ASF1 proteins shared most of the interacting partners, we did not observe physical interaction between them, suggesting that in Arabidopsis, two mutually exclusive HIRA complexes may exist depending on whether they include ASF1A or ASF1B.…”

Section: Resultsmentioning

confidence: 99%

Histone chaperone ASF1 mediates H3.3-H4 deposition in Arabidopsis

et al. 2022

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Histone chaperones and chromatin remodelers control nucleosome dynamics, which are essential for transcription, replication, and DNA repair. The histone chaperone Anti-Silencing Factor 1 (ASF1) plays a central role in facilitating CAF-1-mediated replication-dependent H3.1 deposition and HIRA-mediated replication-independent H3.3 deposition in yeast and metazoans. Whether ASF1 function is evolutionarily conserved in plants is unknown. Here, we show that Arabidopsis ASF1 proteins display a preference for the HIRA complex. Simultaneous mutation of both Arabidopsis ASF1 genes caused a decrease in chromatin density and ectopic H3.1 occupancy at loci typically enriched with H3.3. Genetic, transcriptomic, and proteomic data indicate that ASF1 proteins strongly prefers the HIRA complex over CAF-1. asf1 mutants also displayed an increase in spurious Pol II transcriptional initiation and showed defects in the maintenance of gene body CG DNA methylation and in the distribution of histone modifications. Furthermore, ectopic targeting of ASF1 caused excessive histone deposition, less accessible chromatin, and gene silencing. These findings reveal the importance of ASF1-mediated histone deposition for proper epigenetic regulation of the genome.

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“…Studies have indicated that FAM20C might be a biomarker for diverse cancers, including triple-negative breast cancer ( Tagliabracci et al, 2015 ), lung adenocarcinoma ( Li H. et al, 2020 ), and stomach adenocarcinoma ( Liu et al, 2021 ). TLK2 , a nuclear serine-threonine kinase, binds at the H3 binding site to promote ASF1 (histone chaperone protein anti-silencing factor 1) phosphorylation and cell growth ( Simon et al, 2022 ). TLK2 amplifies and serves as an oncogene in multiple diseases ( Kim et al, 2016 ; Lelieveld et al, 2016 ; Kuczler et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of transcriptome characteristics and identification of TLK2 as a potential biomarker in dermatofibrosarcoma protuberans

Zhang

Sun²,

Zheng³

et al. 2022

Front. Genet.

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Background: Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous sarcoma characterized by local invasion and recurrence. RNA sequencing (RNA-seq) allows the qualification of cellular RNA populations and provides information on the transcriptional state. However, few studies have comprehensively analyzed DFSP transcriptional data.Methods: Fourteen DFSP samples with paired non-neoplastic soft tissue from Chinese patients undergoing Mohs micrographic surgery were used for RNA-seq analysis. Differential expression analysis and enrichment analysis for RNA-seq data were performed to identify fusion genes, biomarkers, and microenvironment characteristics of DFSP.Results: This study systemically describes the transcriptomic characteristics of DFSP. First, we performed gene fusion analysis and identified a novel FBN1-CSAD fusion event in a DFSP patient with fibrosarcomatous transformation. Then, we identified TLK2 as a biomarker for DFSP based on functional enrichment analysis, and validated its accuracy for diagnosing DFSP by immunohistochemical staining and joint analysis with public data. Finally, microenvironment analysis described the infiltration characteristics of immune and stromal cells in DFSP.Conclusion: This study demonstrates that RNA-seq can serve as a promising strategy for exploring molecular mechanisms in DFSP. Our results provide new insights into accurate diagnosis and therapeutic targets of DFSP.

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Tousled-like kinase 2 targets ASF1 histone chaperones through client mimicry

Cited by 20 publications

References 89 publications

Investigation of the mechanisms leading to human sperm DNA damage based on transcriptome analysis by RNA-seq techniques

Investigation of the mechanisms leading to human sperm DNA damage based on transcriptome analysis by RNA-seq techniques

Histone chaperone ASF1 mediates H3.3-H4 deposition in Arabidopsis

Comprehensive analysis of transcriptome characteristics and identification of TLK2 as a potential biomarker in dermatofibrosarcoma protuberans

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