Sumoylated Human Histone H4 Prevents Chromatin Compaction by Inhibiting Long-range Internucleosomal Interactions

Dhall, Abhinav; Wei, Sijie; Fierz, Beat; Woodcock, Christopher L.; Lee, Tae Hee; Chatterjee, Champak

doi:10.1074/jbc.m114.591644

Cited by 71 publications

(86 citation statements)

References 52 publications

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“…Supporting this interpretation, fusing bulky moieties to histone proteins interferes with chromatin fiber folding. 60,61 Moreover, expression of H2AX with ubiquitin fused to its C-terminus, which has been associated with transcriptional repression and chromatin compaction, [44][45] suppressed recruitment of endogenous 53BP1 to sites of DNA DSBs (Fig. 4A).…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

et al. 2015

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The mammalian E3 ubiquitin ligases RNF8 and RNF168 facilitate recruitment of the DNA damage response protein 53BP1 to sites of DNA double-strand breaks (DSBs). The mechanism involves recruitment of RNF8, followed by recruitment of RNF168, which ubiquitinates histones H2A/H2AX on K15. 53BP1 then binds to nucleosomes at sites of DNA DSBs by recognizing, in addition to methyl marks, histone H2A/H2AX ubiquitinated on K15. We report here that expressing H2AX fusion proteins with N-terminal bulky moieties can rescue 53BP1 recruitment to sites of DNA DSBs in cells lacking RNF8 or RNF168 or in cells treated with proteasome inhibitors, in which histone ubiquitination at sites of DNA DSBs is compromised. The rescue required S139 at the C-terminus of the H2AX fusion protein and was occasionally accompanied by partial rescue of ubiquitination at sites of DNA DSBs. We conclude that recruitment of 53BP1 to sites of DNA DSBs is possible in the absence of RNF8 or RNF168, but still dependent on chromatin ubiquitination.

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Section: Discussionmentioning

confidence: 99%

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

et al. 2015

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“…Consistent with this mechanism, the stimulatory effect of suH4 did not extend to the demethylation of adjacent MNs and unconjugated free SUMO did not stimulate the LSD1-CoREST complex. The fact that suH4 directly prevents chromatin compaction, 28 but also stimulates the removal of gene-activating histone methylation suggests a model wherein sumoylation may serve as a transient modification to change the methylation state of chromatin (Figure 4). Ultimately, however, suH4 may be removed to facilitate the formation of transcriptionally silenced heterochromatin.…”

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confidence: 99%

Chemically Sumoylated Histone H4 Stimulates Intranucleosomal Demethylation by the LSD1–CoREST Complex

et al. 2017

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Lysine-specific demethylase 1 (LSD1) downregulates eukaryotic gene activity by demethylating mono and dimethylated Lys4 in histone H3. Elucidating the biochemical crosstalk of LSD1 with histone post-translational modifications (PTMs) is essential for developing LSD1-targeted therapeutics in human cancers. We interrogated the small ubiquitin-like modifier (SUMO) driven regulation of LSD1 activity with semisynthetic nucleosomes containing site-specifically methylated and sumoylated histones. We discovered that nucleosomes containing sumoylated histone H4 (suH4), a modification associated with gene repression, stimulate LSD1 activity by a mechanism dependent upon the SUMO-interaction motif in CoREST. Furthermore, the stimulatory effect of suH4 was spatially limited and did not extend to the demethylation of adjacent non-sumoylated nucleosomes. Thus, we have identified histone modification by SUMO as the first PTM that stimulates intranucleosomal demethylation by the developmentally critical LSD1-CoREST complex.

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“…Acetylated H4K12 correlates with euchromatic structure, 60 and sumoylation of the same residue also disrupts chromatin compaction and oligomerization. 61 Modification 6 on H4K12 may disrupt the acetylation or sumoylation of the residue, resulting in misregulation of the dynamics of chromatin structure. These are just some of the growing number of examples of lysine modifications that affect downstream biochemical events.…”

Section: Resultsmentioning

confidence: 99%

Rapid Histone-Catalyzed DNA Lesion Excision and Accompanying Protein Modification in Nucleosomes and Nucleosome Core Particles

Weng

Greenberg

2015

J. Am. Chem. Soc.

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C5′-Hydrogen atoms are frequently abstracted during DNA oxidation. The oxidized abasic lesion 5′-(2-phosphoryl-1,4-dioxobutane) (DOB) is an electrophilic product of the C5′-radical. DOB is a potent irreversible inhibitor of DNA polymerase β, and forms interstrand cross-links in free DNA. We examined the reactivity of DOB within nucleosomes and nucleosome core particles (NCPs), the monomeric component of chromatin. Depending upon the position at which DOB is generated within a NCP, it is excised from nucleosomal DNA at a rate 275–1500-fold faster than that in free DNA. The half-life of DOB (7.0–16.8 min) in NCPs is shorter than any other abasic lesion. DOB’s lifetime in NCPs is also significantly shorter than the estimated lifetime of an abasic site within a cell, suggesting that the observed chemistry would occur intracellularly. Histones also catalyze DOB excision when the lesion is present in the DNA linker region of a nucleosome. Schiff-base formation between DOB and histone proteins is detected in nucleosomes and NCPs, resulting in pyrrolone formation at the lysine residues. The lysines modified by DOB are often post-translationally modified. Consequently, the histone modifications described herein could affect the regulation of gene expression and may provide a chemical basis for the cytotoxicity of the DNA damaging agents that produce this lesion.

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Sumoylated Human Histone H4 Prevents Chromatin Compaction by Inhibiting Long-range Internucleosomal Interactions

Cited by 71 publications

References 52 publications

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168

Chemically Sumoylated Histone H4 Stimulates Intranucleosomal Demethylation by the LSD1–CoREST Complex

Rapid Histone-Catalyzed DNA Lesion Excision and Accompanying Protein Modification in Nucleosomes and Nucleosome Core Particles

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