The extended AT-hook is a novel RNA binding motif

Filarsky, Michael; Zillner, Karina; Araya, Ingrid; Villar-Garea, Ana; Merkl, Rainer; Längst, Gernot; Németh, Attila

doi:10.1080/15476286.2015.1060394

Cited by 46 publications

(53 citation statements)

References 42 publications

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“… Arginine methylation. DNA [ 121 , 124 , 125 , 127 ] Tip5 Bromodomain adjacent to zinc finger domain protein 2A BAZ2A Homo sapiens None Epigenetic rRNA gene silencing. (e) AT 650− GKRGRPRNTEK −660 , 670− KRGRGRPPKVKIT −682 Experimental Exhibits preferential binding towards dsRNA - DNA [ 127 , 227 , 228 ] PTOV1 Prostate tumor-overexpressed gene 1 protein ACID2, PP642 Homo sapiens None Regulation of transcription.…”

Section: The Coming Of Age For Rna-binding Proteins — the Emerging Romentioning

confidence: 99%

“… (e) AT 650− GKRGRPRNTEK −660 , 670− KRGRGRPPKVKIT −682 Experimental Exhibits preferential binding towards dsRNA - DNA [ 127 , 227 , 228 ] PTOV1 Prostate tumor-overexpressed gene 1 protein ACID2, PP642 Homo sapiens None Regulation of transcription. (e) AT 1− MVRPRRAPYRSGAGG PLGGRGRPPRPLVVR AVRSRSWPASPRG −43 Predicted Exhibits preferential binding towards dsRNA Alternative splicing a DNA [ 127 ] GPBP1 - Vasculin, GPBP, SSH6 Homo sapiens None Transcription factor, positive regulation of transcription e (AT) 38− NRYDVNRRRHNSSDG FDSAIGRPNGGNFGR KEKNGWRTHGRNG −80 Predicted Exhibits preferential binding towards dsRNA Alternative splicing a DNA [ 127 ] SRSF2 Serine/arginine-rich splicing factor 2 SFRS2 Homo sapiens 1xRRM RNA splicing. Other (GRP) 1− MSYGRPPP −8 , 93− GRPPDSHHS −101 Experimental UCCA/UG, UGGA/UG - [ 229 , 230 ] Tra2-β1 Transformer-2 protein homolog beta TRA2B, SFRS10 Homo sapiens 1xRRM RNA splicing.…”

Section: The Coming Of Age For Rna-binding Proteins — the Emerging Romentioning

confidence: 99%

“…Preferentially binds snoRNA. - - [ 127 , 240 ] Ezh2 Histone-lysine N-methyltransferase EZH2 Enx1h Mus musculus None Polycomb group protein. Involved in H3 methylation (H3K9me and H3K27me).…”

Section: The Coming Of Age For Rna-binding Proteins — the Emerging Romentioning

confidence: 99%

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The new (dis)order in RNA regulation

et al. 2016

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RNA-binding proteins play a key role in the regulation of all aspects of RNA metabolism, from the synthesis of RNA to its decay. Protein-RNA interactions have been thought to be mostly mediated by canonical RNA-binding domains that form stable secondary and tertiary structures. However, a number of pioneering studies over the past decades, together with recent proteome-wide data, have challenged this view, revealing surprising roles for intrinsically disordered protein regions in RNA binding. Here, we discuss how disordered protein regions can mediate protein-RNA interactions, conceptually grouping these regions into RS-rich, RG-rich, and other basic sequences, that can mediate both specific and non-specific interactions with RNA. Disordered regions can also influence RNA metabolism through protein aggregation and hydrogel formation. Importantly, protein-RNA interactions mediated by disordered regions can influence nearly all aspects of co- and post-transcriptional RNA processes and, consequently, their disruption can cause disease. Despite growing interest in disordered protein regions and their roles in RNA biology, their mechanisms of binding, regulation, and physiological consequences remain poorly understood. In the coming years, the study of these unorthodox interactions will yield important insights into RNA regulation in cellular homeostasis and disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-016-0132-3) contains supplementary material, which is available to authorized users.

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Section: The Coming Of Age For Rna-binding Proteins — the Emerging Romentioning

confidence: 99%

Section: The Coming Of Age For Rna-binding Proteins — the Emerging Romentioning

confidence: 99%

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The new (dis)order in RNA regulation

et al. 2016

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“…It should also be noted that only AT‐Hook1 has the glycine‐arginine‐proline core tripeptide of the canonical AT‐Hook domain (Aravind & Landsman, ). Additionally, recent studies have suggested that a sub‐population of canonical AT‐Hook domains with extended flanking basic amino acid residues may have RNA‐binding properties in addition to DNA binding, and that MECP2 AT‐Hook1 belongs to this “extended” AT‐Hook (eAT‐Hook) class (Filarsky et al., ).…”

Section: Discussionmentioning

confidence: 99%

MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

et al. 2018

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Mutations in the methyl-CpG-binding protein-2 gene (MECP2) are commonly associated with Rett syndrome. However, it has long been appreciated that there exists a spectrum of neuropsychiatric phenotypes associated with MECP2 variants. The most frequent Rett missense mutations are located in either the methyl-CpG-binding domain (MBD) or transcription repression domain (TRD). Clinical roles for mutations in other domains such as the intervening domain (ID) or AT-Hook domains have yet to be determined. Here, we report functional analysis of MECP2 missense mutations, located in AT-Hook1 within the ID, in a large Pakistani family with childhood onset cognitive decline and schizophrenia (SCZ), de novo in a girl with atypical Rett syndrome, and de novo in a woman with SCZ. We show that both p.Arg190His and p.Arg190Cys affect the ability of MeCP2 to bind to AT-rich DNA, also the brain-derived neurotrophic factor (BDNF) promoter, with the more drastic effects seen for p.Arg190Cys. Both mutations also affect nuclear chromatin clustering in vitro. These data support a possible molecular link between MECP2 AT-Hook1 mutations and psychosis. Given the ongoing large-scale whole exome and whole genome sequencing projects for psychiatric disorders, our findings suggest that rare missense variants in MECP2 be carefully evaluated for molecular consequences.

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“…A central consensus sequence of glycine-arginine-proline (GRP) allows the motif to insert into the minor groove of DNA. In addition, the extended AThook has been shown to bind to RNA [20]. AT-hooks prefer AT-rich DNA sequences as this leads to narrowing of the minor groove and a more focused electrostatic potential [21,22].…”

mentioning

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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The extended AT-hook is a novel RNA binding motif

Cited by 46 publications

References 42 publications

The new (dis)order in RNA regulation

The new (dis)order in RNA regulation

MeCP2 AT-Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

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

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