Histone Ubiquitination: Triggering Gene Activity

Weake, Vikki M.; Workman, Jerry L.

doi:10.1016/j.molcel.2008.02.014

Cited by 606 publications

(611 citation statements)

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“…Notably, H2B monoubiquitylation was subsequently found to be required for di-and trimethylation of lysine 4 and lysine 79 of histone H3 at transcribed chromatin [42][43][44][45][46][47][48]. This pathway is conserved from yeast to mammals, and is dependent on a host of additional proteins that converge at the elongating RNA Pol II [41,[49][50][51][52][53][54]. Subsequently, the mammalian orthologs of the yeast Bre1, RNF20 and RNF40, were identified [55,56].…”

Section: Open Access Under CC By-nc-nd Licensementioning

confidence: 99%

“…An important example of the involvement in the DDR of another histone mark that is normally associated with gene regulation is histone H2A monoubiquitylation, which was linked to transcription silencing (reviewed in [41,109]). This process was recently implicated in facilitating DSB repair and was associated with two DDR players, the RING finger proteins RNF8 and RNF168 [15,[110][111][112][113][114][115].…”

Section: Rnf20-rnf40 Is Called To Emergency Action Upon Dna Damage Inmentioning

confidence: 99%

“…Monoubiquitylated histone H2B: from general to highly specific transcription regulator Ubiquitylation of histone H2B in mammalian cells was identified over three decades ago [37], but more than two decades passed before the function of this modification in regulating mammalian chromatin-associated processes was deciphered. The first breakthrough came with the identification of the budding yeast protein Bre1 [38,39], which, together with the ubiquitin-conjugating enzyme Rad6, serves as the E3 ligase in the monoubiquitylation of the yeast histone H2B on lysine 123 (K123) within transcribed chromatin [38][39][40][41]. Notably, H2B monoubiquitylation was subsequently found to be required for di-and trimethylation of lysine 4 and lysine 79 of histone H3 at transcribed chromatin [42][43][44][45][46][47][48].…”

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confidence: 99%

“…Thus, while carrying out its regular enzymatic activity in the DDR context, it was presumably physically and functionally detached from its regular context. In the transcription context, H2B monoubiquitylation in yeast and mammals is dependent on the early steps in transcription initiation and elongation, and the corresponding E3 ligase closely interacts with many proteins that take part in this process, some of which associate directly with RNA Pol II [41,[49][50][51][52][53][54]99,100]. It is not entirely clear how many of the proteins surrounding RNF20-RNF40 in the transcription context accompany this heterodimer to the DNA damage sites.…”

mentioning

confidence: 99%

“…Fierz et al [70] recently showed that this modification interferes with compaction of the 30 nm chromatin fiber and leads to an open, biochemically accessible fiber conformation. This conformation may facilitate nucleosome dis-and reassembly during transcription and repair, enhancing the accessibility of DNA embedded in chromatin to the corresponding enzymes in these various DNA transactions.An important example of the involvement in the DDR of another histone mark that is normally associated with gene regulation is histone H2A monoubiquitylation, which was linked to transcription silencing (reviewed in [41,109]). This process was recently implicated in facilitating DSB repair and was associated with two DDR players, the RING finger proteins RNF8 and RNF168 [15,[110][111][112][113][114][115].…”

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RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

et al. 2011

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a b s t r a c tThe DNA damage response (DDR) is emerging as a vast signaling network that temporarily modulates numerous aspects of cellular metabolism in the face of DNA lesions, especially critical ones such as the double strand break (DSB). The DDR involves extensive dynamics of protein post-translational modifications, most notably phosphorylation and ubiquitylation. The DSB response is mobilized primarily by the ATM protein kinase, which phosphorylates a plethora of key players in its various branches. It is based on a core of proteins dedicated to the damage response, and a cadre of proteins borrowed temporarily from other cellular processes to help meet the challenge. A recently identified novel component of the DDR pathway -histone H2B monoubiquitylationexemplifies this principle. In mammalian cells, H2B monoubiquitylation is driven primarily by an E3 ubiquitin ligase composed of the two RING finger proteins RNF20 and RNF40. Generation of monoubiquitylated histone H2B (H2Bub) has been known to be coupled to gene transcription, presumably modulating chromatin decondensation at transcribed regions. New evidence indicates that the regulatory function of H2Bub on gene expression can selectively enhance or suppress the expression of distinct subsets of genes through a mechanism involving the hPAF1 complex and the TFIIS protein. This delicate regulatory process specifically affects genes that control cell growth and genome stability, and places RNF20 and RNF40 in the realm of tumor suppressor proteins. In parallel, it was found that following DSB induction, the H2B monoubiquitylation module is recruited to damage sites where it induces local H2Bub, which in turn is required for timely recruitment of DSB repair protein and, subsequently, timely DSB repair. This pathway represents a crossroads of the DDR and chromatin organization, and is a typical example of how the DDR calls to action functional modules that in unprovoked cells regulate other processes. Ó 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. The DNA damage response: borrowing functional modules in an emergencyCellular metabolism is controlled by numerous, interlocked signaling networks. These networks are constantly responding to internal and external stimuli related to the cell's normal life cycle and functions, and to threats to its well being. A major threat to cellular homeostasis is subversion of its genomic stability, which may lead to undue cell death or to neoplasia [1,2]. DNA damage caused by internal or external damaging agents is a major danger to the integrity of the cellular genome. The cellular defense system against this threat is the DNA damage response (DDR) -an elaborate signaling network activated by DNA damage, which swiftly modulates many physiological processes [3,4]. A strong trigger of the DDR is the DNA double-strand break (DSB) [5,6]. DSBs are induced by ionizing radiation, radiomimetic chemicals, reactive oxygen species formed in the course of normal metabolism, and can also result from replic...

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Section: Open Access Under CC By-nc-nd Licensementioning

confidence: 99%

Section: Rnf20-rnf40 Is Called To Emergency Action Upon Dna Damage Inmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

et al. 2011

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Touch and go: nuclear proteolysis in the regulation of metabolic genes and cancer

Maneix

Catic

2016

FEBS Letters

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The recruitment of transcription factors to promoters and enhancers is a critical step in gene regulation. Many of these proteins are quickly removed from DNA after they completed their function. Metabolic genes in particular are dynamically regulated and continuously adjusted to cellular requirements. Transcription factors controlling metabolism are therefore under constant surveillance by the ubiquitin-proteasome system, which can degrade DNA-bound proteins in a site-specific manner. Several of these metabolic transcription factors are critical to cancer cells, as they promote uncontrolled growth and proliferation. This review highlights recent findings in the emerging field of nuclear proteolysis and outlines novel paradigms for cancer treatment, with an emphasis on multiple myeloma.

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Co‐occurrence of BAP1 and SF3B1 mutations in uveal melanoma induces cellular senescence

Zhou

Zhang

et al. 2021

Molecular Oncology

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Uveal melanoma (UM) is the most common intraocular tumor in adults. Recurrent mutations in BRCA1‐associated protein 1 (BAP1) and splicing factor 3B subunit 1 (SF3B1) display a mutually exclusive pattern in UM, but the underlying mechanism is unknown. We show that combined BAP1 deficiency and SF3B1 hotspot mutation lead to senescence and growth arrest in human UM cells. Although p53 protein expression is induced, deletion of TP53 (encoding p53) only modestly rescues the observed senescent phenotype. UM cells with BAP1 loss or SF3B1 mutation are more sensitive to chemotherapeutic drugs compared with their isogenic parental cells. Transcriptome analysis shows that DNA‐repair genes are downregulated upon co‐occurrence of BAP1 deletion and SF3B1 mutation, thus leading to impaired DNA damage response and the induction of senescence. The co‐occurrence of these two mutations reduces invasion of UM cells in zebrafish xenograft models and suppresses growth of melanoma xenografts in nude mice. Our findings provide a mechanistic explanation for the mutual exclusivity of BAP1 and SF3B1 mutations in human UM.

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Histone Ubiquitination: Triggering Gene Activity

Cited by 606 publications

References 96 publications

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

Touch and go: nuclear proteolysis in the regulation of metabolic genes and cancer

Co‐occurrence of BAP1 and SF3B1 mutations in uveal melanoma induces cellular senescence

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