Beyond the marks: reader-effectors as drivers of epigenetics and chromatin engineering

Franklin, Kierra A.; Shields, Cara E.; Haynes, Karmella A.

doi:10.1016/j.tibs.2022.03.002

Cited by 17 publications

(12 citation statements)

References 99 publications

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“…One of the most prominent interactors in the chromatin biology cluster is YEATS2, a histone crotonylation and acetylation reader that forms part of the ADA Two A-Containing (ATAC) histone acetyltransferase complex [81][82][83][84]. YEATS2 is required for transcriptional activation of ATAC target genes [85]. This result could indicate that SLX4 is also involved in activating these target genes; additional links between SLX4 and gene transcription are discussed below.…”

Section: Connections Between Slx4 and Chromatin Biologymentioning

confidence: 99%

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Aprosoff

Dyakov

Cheung

et al. 2022

Preprint

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The DNA repair scaffold SLX4 has pivotal roles in cellular processes that maintain genome stability, most notably homologous recombination. Germline mutations in SLX4 are associated with Fanconi anemia, a disease characterized by chromosome instability and cancer susceptibility. The role of mammalian SLX4 in homologous recombination depends critically on binding and activating structure-selective endonucleases, namely SLX1, MUS81-EME1, and XPF-ERCC1. Increasing evidence indicates that cells rely on distinct SLX4-dependent complexes to remove DNA lesions in specific regions of the genome. Despite our understanding of SLX4 as a scaffold for DNA repair proteins, a detailed repertoire of SLX4 interactors has never been reported. Here, we provide the first comprehensive map of the human SLX4 interactome using proximity-dependent biotin identification (BioID) and affinity purification coupled to mass spectrometry (AP-MS). We identified 237 high-confidence interactors, of which the vast majority represent novel SLX4 binding proteins. Network analysis of these hits revealed pathways with known involvement of SLX4, such as DNA repair, and novel or emerging pathways of interest, including RNA metabolism and chromatin remodeling. In summary, the comprehensive SLX4 interactome we report here provides a deeper understanding of how SLX4 functions in DNA repair while revealing new cellular processes that may involve SLX4.

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Section: Connections Between Slx4 and Chromatin Biologymentioning

confidence: 99%

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Aprosoff

Dyakov

Cheung

et al. 2022

Preprint

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“…Generally, histone deacetylation is followed by the onset of repressing modifications (e.g., H3K9me2, H3K27me3) which promote the recruitment of additional repressors to further condensate the nucleosome structure. The final goal is to impede the binding of TFs and to prevent transcription ( Aloia, 2022 ; Franklin et al, 2022 ).…”

Section: Hdac4 As a Platform To Coordinate Multiple Tasksmentioning

confidence: 99%

HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications

Cuttini

Goi

Pellarin

et al. 2023

Front. Mol. Biosci.

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Controlling access to genomic information and maintaining its stability are key aspects of cell life. Histone acetylation is a reversible epigenetic modification that allows access to DNA and the assembly of protein complexes that regulate mainly transcription but also other activities. Enzymes known as histone deacetylases (HDACs) are involved in the removal of the acetyl-group or in some cases of small hydrophobic moieties from histones but also from the non-histone substrate. The main achievement of HDACs on histones is to repress transcription and promote the formation of more compact chromatin. There are 18 different HDACs encoded in the human genome. Here we will discuss HDAC4, a member of the class IIa family, and its possible contribution to cancer development.

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“…The atomic coordinates and structure factors for the ATAD2B BRD in complex with histone H4K12ac (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), H4S1phK5ac (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), and H4S1CK5ac (1-15) have been deposited in PDB and will be made available upon publication. The CUT&RUN data will also be made available through the NCBI GEO database upon publication.…”

Section: Data Availabilitymentioning

confidence: 99%

“…The atomic coordinates and structure factors for the ATAD2B BRD in complex with histone H4K12ac (4-17), H4S1phK5ac (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), and H4S1CK5ac (1-15) have been deposited with the Protein Data Bank under the accession numbers -8EOQ, 8ESJ, and 7TZQ respectively.…”

Section: Data Availabilitymentioning

confidence: 99%

“…Distinctive combinations of multiple types of histone PTMs can be present simultaneously on histones, commonly referred to form a 'histone code' (6). These unique patterns of histone PTMs can serve as binding sites for a variety of effector proteins that can translate the histone code into biological readouts that include the activation and repression of the gene expression (6)(7)(8). Despite intensive research to understand the different histone 'reader' proteins that selectively recognize individual PTMs, little is known about the combinatorial recognition of different histone modifications.…”

Section: Introductionmentioning

confidence: 99%

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Impact of combinatorial histone modifications on acetyllysine recognition by the ATAD2 and ATAD2B bromodomains

Phillips

Quinn

Paculova

et al. 2022

Preprint

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The ATPase family, AAA domain containing 2B (ATAD2B) protein has a C-terminal bromodomain that functions as a reader of acetylated lysine residues on histone proteins. However, the molecular mechanisms by which it recognizes chromatin with multiple post-translational modifications remain poorly understood. To gain insights into the recognition of acetylated lysines by the ATAD2B bromodomain, we investigated the recognition of combinatorial histone H4 post-translational modifications using structural and functional approaches. Using isothermal titration calorimetry, we assessed the binding affinities of the ATAD2B bromodomain with distinct histone H4 peptides harboring multiple modifications. Our results show that the ATAD2B bromodomain selectively recognizes acetyllysine residues amongst multiple histone H4 modifications. Most of these adjacent modifications are permissive and exhibit distinctive binding affinities, however, some combinations weaken the acetyllysine interaction. Three novel protein-ligand structures reveal a unique binding mode for the ATAD2B bromodomain compared to the ATAD2 bromodomain, and highlight distinctive residues involved in the coordination of acetylated lysines in the context of adjacent post-translational modifications. To investigate the association of ATAD2B with chromatin, we performed CUT&RUN experiments in human breast cancer cells and compared the genome-wide chromatin binding sites to different regulatory histone modifications. Our results support an association of ATAD2B with endogenous acetylated histone H4. Overall, our study highlights how the interplay between various histone modifications, and combinations thereof, impact the reader activity of the ATAD2B bromodomain.

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Beyond the marks: reader-effectors as drivers of epigenetics and chromatin engineering

Cited by 17 publications

References 99 publications

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

Comprehensive Interactome Mapping of the DNA Repair Scaffold SLX4 using Proximity Labeling and Affinity Purification

HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications

Impact of combinatorial histone modifications on acetyllysine recognition by the ATAD2 and ATAD2B bromodomains

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