Structural and biophysical characterization of the nucleosome-binding PZP domain

Klein, Brianna J.; Cox, Khan L.; Jang, Suk Min; Singh, Rohit; Côté, Jacques; Poirier, Michael G.; Kutateladze, Tatiana G.

doi:10.1016/j.xpro.2021.100479

Cited by 5 publications

(5 citation statements)

References 25 publications

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“…For purification of native complexes, after large-scale expansion of K562 clones, affinity purifications of tagged MORF N WT (aa 2–716), ΔWH1 (aa 86–716), ΔWH2 (aa 2–99 + aa 183–716) and ΔWH1/2 (aa 183–716), were performed on nuclear extracts as previously described 59 . Briefly, nuclear extracts were prepared following standard procedures and pre-cleared with CL6B Sepharose beads.…”

Section: Methodsmentioning

confidence: 99%

MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain

et al. 2023

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Human acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities.

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Section: Methodsmentioning

confidence: 99%

MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain

et al. 2023

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“…Therefore, the biophysical properties of each chromosomal component, including DNA, nucleosomes, and chromatin, are essential for the analysis of such hierarchy in chromosomes. [14][15][16] Additionally, due to structural complexity and technological limitations, 1,[17][18][19][20] the question remains open as to how the human mitotic chromosomes are specically condensed at each stage, including the interphase, prophase, metaphase, anaphase, and telophase. Although extensive microscopic studies revealed the condensed supramolecular structure of metaphase chromosomes, 1,18,21 their detailed biophysical characteristics such as surface charge and nanomechanical mapping are still elusive.…”

Section: Introductionmentioning

confidence: 99%

Direct observation of surface charge and stiffness of human metaphase chromosomes

et al. 2023

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“…Tese include the BRPF1 specifc N-terminal (BN) at the N-terminus, enhancer of polycomb (EPC) like motif 1 (EPC-1), plant homeodomain (PHD)-zinc-knuckle-PHD (PZP) module, nuclear localization signal (NLS), EPC-II, a bromodomain, and a Cterminal proline-tryptophan-tryptophan-proline (PWWP) domain [9,[11][12][13][14]. Te EPC-I and BN domains are required for binding to the MYST domain of KAT6A or KAT6B, whereas the PZP domain functions by recognizing histone H3 tails and associating them with DNA [9,[15][16][17]. EPC-II interacts with two accessory proteins, ING5 and MEAF6, while the bromodomain binds to acetyl-lysine in histone H4 and H3 (H4/H3KAc) [18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review

Bayanbold,

Younger,

Darbro

et al. 2023

Case Reports in Genetics

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Bromodomain and PHD finger containing 1 (BRPF1)-related neurodevelopmental disorder is characterized by intellectual disability, developmental delay, hypotonia, dysmorphic facial features, ptosis, and blepharophimosis. Both de novo and inherited pathogenic variants have been previously reported in association with this disorder. We report two affected female siblings with a novel variant in BRPF1 c.2420_2433del (p.Q807Lfs ∗ 27) identified through whole-exome sequencing. Their history of mild intellectual disability, speech delay, attention deficient hyperactivity disorder (ADHD), and ptosis align with the features previously reported in the literature. The absence of the BRPF1 variant in parental buccal samples provides evidence of a de novo frameshift pathogenic variant, most likely as a result of parental gonadal mosaicism, which has not been previously reported. The frameshift pathogenic variant reported here lends further support to haploinsufficiency as the underlying mechanism of disease. We review the literature, compare the clinical features seen in our patients with others reported, and explore the possibility of genotype-phenotype correlation based on the location of pathogenic variants in BRPF1. Our study helps to summarize available knowledge and report the first case of a de novo frameshift pathogenic variant in BRPF1 in two siblings with this neurodevelopmental disorder.

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Structural and biophysical characterization of the nucleosome-binding PZP domain

Cited by 5 publications

References 25 publications

MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain

MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain

Direct observation of surface charge and stiffness of human metaphase chromosomes

Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review

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