The Histone H3-H4 Tetramer is a Copper Reductase Enzyme

Attar, Narsis; Campos, Oscar A.; Vogelauer, Maria; Xue, Yong; Schmollinger, Stefan; Mallipeddi, Nathan V.; Cheng, Chen; Yen, Linda; Yang, Sichen; Zikovich, Shannon; Dardine, Jade; Carey, Michael; Merchant, Sabeeha; Kurdistani, Siavash K.

doi:10.1101/350652

Cited by 10 publications

(15 citation statements)

References 59 publications

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“…Copper ions are known to bind with protein Atox1 in nucleus to regulate gene transcription in vertebrates, 44 and directly activate Cup2 transcriptional activities and suppress Mac1 transcriptional activities in eukaryotes. 45 However, the data in this study failed to provide the solid evidence that Cu ions suppress transcriptional activities of SRF and Myog on smyd1b directly or indirectly. Additionally, it is still unclear which Cu chaperone protein in nucleus mediates Cu ions in suppressing the transcriptional activity of SRF and Myog on smyd1b gene.…”

Section: Cu Ions May Inhibit Myofibrillogenesis Via Downregulating Sm...contrasting

confidence: 67%

Copper ions impair zebrafish skeletal myofibrillogenesis via epigenetic regulation

et al. 2021

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Unbalanced copper (Cu2+) homeostasis is associated with the developmental defects of vertebrate myogenesis, but the underlying molecular mechanisms remain elusive. In this study, it was found that Cu2+ stressed zebrafish embryos and larvae showed reduced locomotor speed as well as loose and decreased myofibrils in skeletal muscle, coupled with the downregulated expression of muscle fiber markers mylpfa and smyhc1l and the irregular arrangement of myofibril and sarcomere. Meanwhile, the Cu2+ stressed zebrafish embryos and larvae also showed significant reduction in the expression of H3K4 methyltransferase smyd1b transcripts and H3K4me3 protein as well as in the binding enrichment of H3K4me3 on gene mylpfa promoter in skeletal muscle cells, suggesting that smyd1b—H3K4me3 axis mediates the Cu2+‐induced myofibrils specification defects. Additionally, whole genome DNA methylation sequencing unveiled that the gene smyd5 exhibited significant promoter hyper‐methylation and increased expression in Cu2+ stressed embryos, and the ectopic expression of smyd5 in zebrafish embryos also induced the myofibrils specification defects as those observed in Cu2+ stressed embryos. Moreover, Cu2+ was shown to suppress myofibrils specification and smyd1b promoter transcriptional activity directly independent of the integral function of copper transporter cox17 and atp7b. All these data may shed light on the linkage of unbalanced copper homeostasis with specific gene promoter methylation and epigenetic histone protein modification as well as the resultant signaling transduction and the myofibrillogenesis defects.

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Section: Cu Ions May Inhibit Myofibrillogenesis Via Downregulating Sm...contrasting

confidence: 67%

Copper ions impair zebrafish skeletal myofibrillogenesis via epigenetic regulation

et al. 2021

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“…Still, as the number of metabolites that can modify histones keeps on growing, e.g., with the recent addition of lactylation (Zhang et al , 2019), an even more complex language starts to surface. For example, histones can also sense cellular metal content (Attar et al , 2020) or become dopaminylated and serotinylated in the brain (Lepack et al , 2020), mediating drug addiction and depression. Yet, while trying to understand the function of so many different hPTMs is challenging in its own right, trying to grasp the emerging complexity of their interplay, i.e., the histone code, is simply overwhelming.…”

Section: Figure Trypsin‐mediated Histone H4 Clipping During Enterocyt...mentioning

confidence: 99%

Histone clipping: the punctuation in the histone code

Dhaenens

2021

EMBO Reports

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Histone clipping was first discovered in the 1960s and still is a lingering mystery. Considering the essential roles of histones in regulating eukaryotic transcription through the histone code, clipping is a post‐translational modification that appeals to the imagination. In this issue of EMBO Reports, Marruecos and colleagues investigate histone H4 clipping during intestinal development (Marruecos et al, 2021), and are providing crucial clues to finally elucidate the intricacies of this elusive modification.

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“…The Cu-Zn superoxide dismutase, Sod1, is a major contributor to antioxidant defense and is likely to protect Fe-S clusters from damage in the presence of oxygen (51). We previously found that H3H113N diminishes Sod1 activity (24). However, in the unique context of YFH1-off and the resulting decrease of Fe-S clusters, we considered whether the restoration of function by H3H113N depended on Sod1.…”

Section: H3h113n When Fe-s Cluster Assembly Is Disruptedmentioning

confidence: 99%

A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich’s Ataxia

Campos

Attar

et al. 2021

Preprint

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Disruptions to iron-sulfur (Fe-S) clusters, essential cofactors for a broad range of proteins, cause widespread cellular defects resulting in human disease. An underappreciated source of damage to Fe-S clusters are cuprous (Cu1+) ions. Since histone H3 enzymatically produces Cu1+ to support copper-dependent functions, we asked whether this activity could become detrimental to Fe-S clusters. Here, we report that histone H3-mediated Cu1+ toxicity is a major determinant of cellular Fe-S cluster quotient. Inadequate Fe-S cluster supply, either due to diminished assembly as occurs in Friedreich's Ataxia or defective distribution, causes severe metabolic and growth defects in S. cerevisiae. Decreasing Cu1+ abundance, through attenuation of histone cupric reductase activity or depletion of total cellular copper, restored Fe-S cluster-dependent metabolism and growth. Our findings reveal a novel interplay between chromatin and mitochondria in Fe-S cluster homeostasis, and a potential pathogenic role for histone enzyme activity and Cu1+ in diseases with Fe-S cluster dysfunction.

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The Histone H3-H4 Tetramer is a Copper Reductase Enzyme

Abstract: 28Ancestral histones were present in organisms with small genomes, no nucleus and little 29 ability for epigenetic regulation, suggesting histones may have an additional, unknown function. 30We report that the histone H3-H4 tetramer is an enzyme that catalyzes the reduction of Cu 2+ to

Cited by 10 publications

References 59 publications

Copper ions impair zebrafish skeletal myofibrillogenesis via epigenetic regulation

Copper ions impair zebrafish skeletal myofibrillogenesis via epigenetic regulation

Histone clipping: the punctuation in the histone code

A pathogenic role for histone H3 copper reductase activity in a yeast model of Friedreich’s Ataxia

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