The ATPase SRCAP is associated with the mitotic apparatus, uncovering novel molecular aspects of Floating-Harbor syndrome

Messina, Giovanni; Prozzillo, Yuri; Monache, Francesca Delle; Santopietro, Maria Virginia; Atterrato, Maria Teresa; Dimitri, Patrizio

doi:10.1186/s12915-021-01109-x

Cited by 16 publications

(31 citation statements)

References 61 publications

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“…In contrast, this is not observed upon VPS72 downregulation. These observations support previous findings where INO80 [ 70 ] and SRCAP [ 71 ] associate with the spindle apparatus and are required for proper mitotic progression. To our knowledge EP400 has not been linked to spindle function yet.…”

Section: Resultssupporting

confidence: 92%

LiveCellMiner: A new tool to analyze mitotic progression

et al. 2022

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Live-cell imaging has become state of the art to accurately identify the nature of mitotic and cell cycle defects. Low- and high-throughput microscopy setups have yield huge data amounts of cells recorded in different experimental and pathological conditions. Tailored semi-automated and automated image analysis approaches allow the analysis of high-content screening data sets, saving time and avoiding bias. However, they were mostly designed for very specific experimental setups, which restricts their flexibility and usability. The general need for dedicated experiment-specific user-annotated training sets and experiment-specific user-defined segmentation parameters remains a major bottleneck for fully automating the analysis process. In this work we present LiveCellMiner, a highly flexible open-source software tool to automatically extract, analyze and visualize both aggregated and time-resolved image features with potential biological relevance. The software tool allows analysis across high-content data sets obtained in different platforms, in a quantitative and unbiased manner. As proof of principle application, we analyze here the dynamic chromatin and tubulin cytoskeleton features in human cells passing through mitosis highlighting the versatile and flexible potential of this tool set.

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Section: Resultssupporting

confidence: 92%

LiveCellMiner: A new tool to analyze mitotic progression

et al. 2022

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“…In a previous report, we have found that the ATPase SRCAP interacts with a plethora of cytokinesis regulators and positively controls their recruitment to the midbody [ 31 ].…”

Section: Resultsmentioning

confidence: 99%

“…IN = input, IP = immunoprecipitation. Synchronization of the HeLa cells was performed according to Messina et al [ 31 ]. B Histograms showing the quantitative analysis of mislocalizations of cytokinesis regulators at the midbody in mocks and BAF53a or Tip60 depleted cells.…”

Section: Resultsmentioning

confidence: 99%

“…However, little is known about relevance and evolutionary conservation of this phenomenon. We have recently found that the ATPase SRCAP, the main subunit of the SRCAP complex, which is implicated in the Floating Harbor syndrome [ 30 ], associates with components of the mitotic apparatus (centrosomes, spindle, midbody), interacts with a plethora of cytokinesis regulators, and positively controls their recruitment to the midbody [ 31 ]. Remarkably, SRCAP depletion perturbs both mitosis and cytokinesis.…”

Section: Introductionmentioning

confidence: 99%

“…Remarkably, SRCAP depletion perturbs both mitosis and cytokinesis. Similarly, DOM-A, the functional SRCAP orthologue of Drosophila melanogaster , is found at centrosomes and the midbody in this model organism and its depletion affects cell division [ 31 ]. Together our findings suggested that SRCAP ensures proper chromosome segregation during mitosis and midbody function during cytokinesis.…”

Section: Introductionmentioning

confidence: 99%

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Evolutionary conserved relocation of chromatin remodeling complexes to the mitotic apparatus

et al. 2022

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Background ATP-dependent chromatin remodeling complexes are multi-protein machines highly conserved across eukaryotic genomes. They control sliding and displacing of the nucleosomes, modulating histone-DNA interactions and making nucleosomal DNA more accessible to specific binding proteins during replication, transcription, and DNA repair, which are processes involved in cell division. The SRCAP and p400/Tip60 chromatin remodeling complexes in humans and the related Drosophila Tip60 complex belong to the evolutionary conserved INO80 family, whose main function is promoting the exchange of canonical histone H2A with the histone variant H2A in different eukaryotic species. Some subunits of these complexes were additionally shown to relocate to the mitotic apparatus and proposed to play direct roles in cell division in human cells. However, whether this phenomenon reflects a more general function of remodeling complex components and its evolutionary conservation remains unexplored. Results We have combined cell biology, reverse genetics, and biochemical approaches to study the subcellular distribution of a number of subunits belonging to the SRCAP and p400/Tip60 complexes and assess their involvement during cell division progression in HeLa cells. Interestingly, beyond their canonical chromatin localization, the subunits under investigation accumulate at different sites of the mitotic apparatus (centrosomes, spindle, and midbody), with their depletion yielding an array of aberrant outcomes of mitosis and cytokinesis, thus causing genomic instability. Importantly, this behavior was conserved by the Drosophila melanogaster orthologs tested, despite the evolutionary divergence between fly and humans has been estimated at approximately 780 million years ago. Conclusions Overall, our results support the existence of evolutionarily conserved diverse roles of chromatin remodeling complexes, whereby subunits of the SRCAP and p400/Tip60 complexes relocate from the interphase chromatin to the mitotic apparatus, playing moonlighting functions required for proper execution of cell division.

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Missense variant in SRCAP with distinct DNA methylation signature associated with non‐FLHS SRCAP‐related neurodevelopmental disorder

White‐Brown,

Choufani,

Weksberg

et al. 2023

American J of Med Genetics Pt A

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Floating‐Harbor syndrome (FLHS) is a neurodevelopmental disorder (NDD) caused by truncating variants in exons 33 and 34 of the SNF2‐related CREBBP activator protein gene (SRCAP). Truncating variants proximal to this location in SRCAP result in a non‐FLHS SRCAP‐associated NDD; an overlapping but distinct NDD characterized by developmental delay with or without intellectual disability (ID), hypotonia, normal stature, and behavioral and psychiatric issues. Here, we report a young woman who initially presented in childhood with significant delays in speech and mild ID. In young adulthood, she developed schizophrenia. On physical examination, she had facial features suggestive of 22q11 deletion syndrome. After non‐diagnostic chromosomal microarray and trio exome sequencing (ES), a re‐analysis of trio ES data identified a de novo missense variant in SRCAP that was proximal to the FLHS critical region. Subsequent DNA methylation studies showed the unique methylation signature associated with pathogenic sequence variants in non‐FLHS SRCAP‐related NDD. This clinical report describes an individual with non‐FLHS SRCAP‐related NDD caused by an SRCAP missense variant, and it also demonstrates the clinical utility of ES re‐analysis and DNA methylation analysis for undiagnosed patients, in particular, those with variants of uncertain significance.

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The ATPase SRCAP is associated with the mitotic apparatus, uncovering novel molecular aspects of Floating-Harbor syndrome

Cited by 16 publications

References 61 publications

LiveCellMiner: A new tool to analyze mitotic progression

LiveCellMiner: A new tool to analyze mitotic progression

Evolutionary conserved relocation of chromatin remodeling complexes to the mitotic apparatus

Missense variant in SRCAP with distinct DNA methylation signature associated with non‐FLHS SRCAP‐related neurodevelopmental disorder

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