Dynamic phosphorylation of Histone Deacetylase 1 by Aurora kinases during mitosis regulates zebrafish embryos development

Loponte, Sara; Segré, Chiara V.; Senese, Silvia; Miccolo, Claudia; Santaguida, Stefano; Deflorian, Gianluca; Citro, Simona; Mattoscio, Domenico; Pisati, Federica; Moser, M.; Visintin, Rosella; Seiser, Christian; Chiocca, Susanna

doi:10.1038/srep30213

Cited by 14 publications

(16 citation statements)

References 40 publications

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“…We thus screened for RSF1-interacting proteins using tandem affinity purification followed by mass spectrometry analysis, which indicated HDAC1 as a potential RSF1-binding protein (Supplementary Data 1 ). Although the transcriptional function of HDAC1 has been studied extensively 34 – 36 , its subcellular localization and function in mitosis was partly shown 37 , 38 . Flag-HDAC1 bound to GST-RSF1 in human cell lysates, and the interaction between these proteins was maintained in asynchronously growing cells (mainly interphase) and mitotic cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

The chromatin remodeler RSF1 controls centromeric histone modifications to coordinate chromosome segregation

et al. 2018

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Chromatin remodelers regulate the nucleosome barrier during transcription, DNA replication, and DNA repair. The chromatin remodeler RSF1 is enriched at mitotic centromeres, but the functional consequences of this enrichment are not completely understood. Shugoshin (Sgo1) protects centromeric cohesion during mitosis and requires BuB1-dependent histone H2A phosphorylation (H2A-pT120) for localization. Loss of Sgo1 at centromeres causes chromosome missegregation. Here, we show that RSF1 regulates Sgo1 localization to centromeres through coordinating a crosstalk between histone acetylation and phosphorylation. RSF1 interacts with and recruits HDAC1 to centromeres, where it counteracts TIP60-mediated acetylation of H2A at K118. This deacetylation is required for the accumulation of H2A-pT120 and Sgo1 deposition, as H2A-K118 acetylation suppresses H2A-T120 phosphorylation by Bub1. Centromeric tethering of HDAC1 prevents premature chromatid separation in RSF1 knockout cells. Our results indicate that RSF1 regulates the dynamics of H2A histone modifications at mitotic centromeres and contributes to the maintenance of chromosome stability.

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Section: Resultsmentioning

confidence: 99%

The chromatin remodeler RSF1 controls centromeric histone modifications to coordinate chromosome segregation

et al. 2018

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“…The mechanism of resistance to aurora kinase inhibitors is also unclear, although of note, both aurora kinase A and B has been shown to phosphorylate HDAC1. Therefore aurora kinase is implicated in the maintenance of HDAC enzymatic activity [49] . The relative resistance to aurora kinase inhibition identified by the screen is also in direct contrast with the preferential pre-clinical sensitivity of MYCN amplified neuroblastoma to aurora kinase A inhibitors [50] , emphasizing the importance of molecular pre-selection for trials of novel agents in neuroblastoma patients.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma

et al. 2020

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Background In neuroblastoma, genetic alterations in ATRX, define a distinct poor outcome patient subgroup. Despite the need for new therapies, there is a lack of available models and a dearth of pre-clinical research. Methods To evaluate the impact of ATRX loss of function (LoF) in neuroblastoma, we utilized CRISPR-Cas9 gene editing to generate neuroblastoma cell lines isogenic for ATRX . We used these and other models to identify therapeutically exploitable synthetic lethal vulnerabilities associated with ATRX LoF. Findings In isogenic cell lines, we found that ATRX inactivation results in increased DNA damage, homologous recombination repair (HRR) defects and impaired replication fork processivity. In keeping with this, high-throughput compound screening showed selective sensitivity in ATRX mutant cells to multiple PARP inhibitors and the ATM inhibitor KU60019. ATRX mutant cells also showed selective sensitivity to the DNA damaging agents, sapacitabine and irinotecan. HRR deficiency was also seen in the ATRX deleted CHLA-90 cell line, and significant sensitivity demonstrated to olaparib/irinotecan combination therapy in all ATRX LoF models. In-vivo sensitivity to olaparib/irinotecan was seen in ATRX mutant but not wild-type xenografts. Finally, sustained responses to olaparib/irinotecan therapy were seen in an ATRX deleted neuroblastoma patient derived xenograft. Interpretation ATRX LoF results in specific DNA damage repair defects that can be therapeutically exploited. In ATRX LoF models, preclinical sensitivity is demonstrated to olaparib and irinotecan, a combination that can be rapidly translated into the clinic. Funding This work was supported by Christopher's Smile, Neuroblastoma UK, Cancer Research UK, and the Royal Marsden Hospital NIHR BRC.

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“…With regard to organogenesis, largely studied in zebrafish, histone modifications have been shown to play crucial roles in CNS development, especially the brain (Buschbeck et al, 2009, Tsukada et al, 2010Loponte et al, 2016), specific neuronal ACCEPTED MANUSCRIPT…”

Section: A C C E P T E D Mmentioning

confidence: 99%

Epigenetics in teleost fish: From molecular mechanisms to physiological phenotypes

Best

Ikert

Kostyniuk

et al. 2018

Comparative Biochemistry and Physiology Part B: Biochemistry an

114

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While the field of epigenetics is increasingly recognized to contribute to the emergence of phenotypes in mammalian research models across different developmental and generational timescales, the comparative biology of epigenetics in the large and physiologically diverse vertebrate infraclass of teleost fish remains comparatively understudied. The cypriniform zebrafish and the salmoniform rainbow trout and Atlantic salmon represent two especially important teleost orders, because they offer the unique possibility to comparatively investigate the role of epigenetic regulation in 3R and 4R duplicated genomes. In addition to their sequenced genomes, these teleost species are well-characterized model species for development and physiology, and therefore allow for an investigation of the role of epigenetic modifications in the emergence of physiological phenotypes during an organism's lifespan and in subsequent generations. This review aims firstly to describe the evolution of the repertoire of genes involved in key molecular epigenetic pathways including histone modifications, DNA methylation and microRNAs in zebrafish, rainbow trout, and Atlantic salmon, and secondly, to discuss recent advances in research highlighting a role for molecular epigenetics in shaping physiological phenotypes in these and other teleost models. Finally, by discussing themes and current limitations of the emerging field of teleost epigenetics from both theoretical and technical points of view, we will highlight future research needs and discuss how epigenetics will not only help address basic research questions in comparative teleost physiology, but also inform translational research including aquaculture, aquatic toxicology, and human disease.

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Dynamic phosphorylation of Histone Deacetylase 1 by Aurora kinases during mitosis regulates zebrafish embryos development

Cited by 14 publications

References 40 publications

The chromatin remodeler RSF1 controls centromeric histone modifications to coordinate chromosome segregation

The chromatin remodeler RSF1 controls centromeric histone modifications to coordinate chromosome segregation

Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma

Epigenetics in teleost fish: From molecular mechanisms to physiological phenotypes

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