Reading More than Histones: The Prevalence of Nucleic Acid Binding among Reader Domains

Weaver, Tyler; Morrison, Emma A.; Musselman, Catherine A.

doi:10.3390/molecules23102614

Cited by 53 publications

(49 citation statements)

References 112 publications

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“…23,60 ), and the chromo domain of CBX2 and CBX8 and their homologs with nucleosomes containing H3K27me3 (refs. 2,61 ). Combined histone tail and DNA interactions were also proposed for a double bromodomain in TAF1 (ref.…”

Section: Discussionmentioning

confidence: 99%

Structure of H3K36-methylated nucleosome–PWWP complex reveals multivalent cross-gyre binding

Wang

Farnung

Dienemann

et al. 2019

Nat Struct Mol Biol

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C ovalent modifications of nucleosomes regulate chromatinbased processes such as DNA transcription, replication and repair. Many modifications occur on the accessible histone tails that protrude from the nucleosome core particle. These modifications include acetylation and methylation of lysine residues and are recognized by 'reader' domains that recruit various proteins. The molecular basis for how reader domains recognize histone modifications has been provided by structural studies of reader domain-histone peptide complexes 1 .Some reader domains not only bind modified histone tails, but can additionally bind to DNA. Of over 20 types of reader domains, at least four (PWWP, Tudor, chromo and bromo) are known to bind both the modified histone and DNA 2,3 . These reader domains are predicted to recognize the histone modification in the context of nucleosomal DNA, with both types of interactions contributing to the affinity of the domain for modified nucleosomes. However, such multivalent binding of a reader domain was thus far not observed directly.A widespread type of reader domain that can engage in multivalent interactions is the PWWP (Pro-Trp-Trp-Pro motif) domain. This domain was identified in the protein product of the Wolf-Hirschhorn syndrome candidate gene 1 (WHSC1) and in proteins related to hepatoma-derived growth factor (HDGF) 4,5 . It was later found in the DNA methyltransferase DNMT3B and the DNA repair protein MSH6 (refs. 6,7 ). The PWWP domain is a reader of methylated histone tails and comprises a five-stranded N-terminal β-barrel and two C-terminal α-helices 8 . The β-barrel harbors a conserved aromatic cage that binds a methyl-lysine residue 9 , as also observed for other reader domains of the 'Royal' superfamily such as Tudor, chromo, Agenet and MBT domains 10 .Most PWWP domains bind the histone H3 N-terminal tail that is di-or tri-methylated at lysine 36 (H3K36me2 or H3K36me3) [11][12][13][14][15][16] . The H3K36me3 modification occurs in gene bodies of transcribed chromatin in eukaryotic species from yeast to human 17 . This modification is mainly generated by SETD2 (KMT3A), a lysine methyltransferase associated with elongating RNA polymerase II (Pol II) 18,19 . H3K36me3 has functions in transcription elongation, alternative splicing, DNA methylation, DNA damage signaling, and repression of cryptic transcription and histone exchange 20 .The PWWP domain binds methylated H3K36 histone tail peptides with much lower affinity 11,15 than other methyl-lysine reader domains such as PHD fingers 21 . To achieve high-affinity binding, PWWP domains rely on additional interactions with DNA. Indeed, the PWWP domain was first described as a DNA-binding fold 7,22 , and the PWWP domain in Pdp1 was found to bind both a methylated histone peptide and DNA 23 . Nucleosomal DNA was shown to contribute strongly to high-affinity binding of a PWWP domain to an H3K36-methylated nucleosome 24,25 , and it was predicted that the domain may bind both DNA gyres 25 . Very recently, structures were reported of the PWWP domai...

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Section: Discussionmentioning

confidence: 99%

Structure of H3K36-methylated nucleosome–PWWP complex reveals multivalent cross-gyre binding

Wang

Farnung

Dienemann

et al. 2019

Nat Struct Mol Biol

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“…In addition, several other reader domains (e.g. chromodomains and PWWP domains) that have been identified to bind nucleic acid contain adjacent canonical AT-hooks, AT-like-hooks, extended AT-hooks, or extensions rich in basic residues [55]. Thus, this multivalent mode of interaction may be common.…”

Section: Discussionmentioning

confidence: 99%

The Molecular Basis of Specific DNA Binding by the BRG1 AT-hook and Bromodomain

Sanchez

Zhang

Evoli

et al. 2019

Preprint

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AbstractThe ATP-dependent BAF chromatin remodeling complex plays a critical role in gene regulation by modulating chromatin architecture, and is frequently mutated in cancer. Indeed, subunits of the BAF complex are found to be mutated in >20% of human tumors. The mechanism by which BAF properly navigates chromatin is not fully understood, but is thought to involve a multivalent network of histone and DNA contacts. We previously identified a composite domain in the BRG1 ATPase subunit that is capable of associating with both histones and DNA in a multivalent manner. Mapping the DNA binding pocket revealed that it contains several cancer mutations. Here, we utilize SELEX-seq to identify the DNA specificity of this composite domain and NMR spectroscopy and molecular modelling to determine the structural basis of DNA binding. Finally, we demonstrate that cancer mutations in this domain alter the mode of DNA association.

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“…In addition, PHF1 regulates the deposition of the repressive H3K27me3 mark and functions as a cofactor in the PARP1-and Ku70-Ku80-initiated DNA damage response [106]. Some proteins contain two five-stranded β-barrels connected by a short (3-5 aa) linker termed TTD [108]. Just like JMJD2 family members JMJD2A, JMJD2B, and JMJD2C possess TTD domain, and are capable of removing tri-/di-methylation marks on H3K9 and H3K36 [109].…”

Section: Tudor Domain Proteinsmentioning

confidence: 99%

Small Molecules Targeting the Specific Domains of Histone-Mark Readers in Cancer Therapy

et al. 2020

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Epigenetic modifications (or epigenetic tags) on DNA and histones not only alter the chromatin structure, but also provide a recognition platform for subsequent protein recruitment and enable them to acquire executive instructions to carry out specific intracellular biological processes. In cells, different epigenetic-tags on DNA and histones are often recognized by the specific domains in proteins (readers), such as bromodomain (BRD), chromodomain (CHD), plant homeodomain (PHD), Tudor domain, Pro-Trp-Trp-Pro (PWWP) domain and malignant brain tumor (MBT) domain. Recent accumulating data reveal that abnormal intracellular histone modifications (histone marks) caused by tumors can be modulated by small molecule-mediated changes in the activity of the above domains, suggesting that small molecules targeting histone-mark reader domains may be the trend of new anticancer drug development. Here, we summarize the protein domains involved in histone-mark recognition, and introduce recent research findings about small molecules targeting histone-mark readers in cancer therapy.

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Reading More than Histones: The Prevalence of Nucleic Acid Binding among Reader Domains

Cited by 53 publications

References 112 publications

Structure of H3K36-methylated nucleosome–PWWP complex reveals multivalent cross-gyre binding

Structure of H3K36-methylated nucleosome–PWWP complex reveals multivalent cross-gyre binding

The Molecular Basis of Specific DNA Binding by the BRG1 AT-hook and Bromodomain

Small Molecules Targeting the Specific Domains of Histone-Mark Readers in Cancer Therapy

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