Requirement of ATM-Dependent Monoubiquitylation of Histone H2B for Timely Repair of DNA Double-Strand Breaks

Moyal, Lilach; Lerenthal, Yaniv; Gana‐Weisz, Mali; Mass, Gilad; So, Sairei; Wang, Shih Ya; Eppink, Berina; Chung, Young-Min; Shalev, Gil; Shema, Efrat; Shkedy, Dganit; Smorodinsky, Nechama I.; Vliet, Nicole van; Küster, Bernhard; Mann, Matthias; Ciechanover, Aaron; Dahm-Daphi, Jochen; Kanaar, Roland; Hu, Mickey C.T.; Chen, David J.; Oren, Moshe; Shiloh, Yosef

doi:10.1016/j.molcel.2011.02.015

Cited by 347 publications

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“…Not surprisingly, therefore, damage-induced H2B monoubiquitylation was ATM-and RNF20-RNF40-dependent. Furthermore, this reaction required the presence of ATM's phosphorylation sites in RNF20; replacement of endogenous RNF20 by ectopic, non-phosphorylatable protein abolished the process [90]. On the other hand, end resection and damage-induced release of H2B from chromatin were NBS1-dependent [89].…”

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“…The retardation in DSB repair was observed by indirect readouts such as the disappearance of the nuclear foci of phosphorylated histone H2AX (cH2AX) or the 53BP1 protein, or by direct measurement of DSBs using the I-SceI assay [92,93] or the comet assay [94]. Indeed, H2Bub was found to be induced following DSB induction (the damage-induced H2B monoubiquitylation was seen more clearly when background H2Bub associated with active transcription was reduced using transcription inhibitors [90]). RNF20 was found to be recruited to the damaged sites, suggesting that this process occurred at these sites.…”

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“…Indeed, abrogation of damageinduced H2B monoubiquitylation led to reduced recruitment of players in both pathways to the damage sites [89,90]. Notably, H2Bub formation was not required for the initial recruitment of players in the ''sensor'' layer of the DDR [89,90] but was specifically needed for recruiting the repair proteins, and was thus independent of cH2AX formation [89].The temporary anchoring of RNF20-RNF40 at damage sites may be due to interactions with other damage response proteins that accumulate at these sites, including the basal interactions with ATM and NBS1 [89,90]. This temporary residence of RNF20-RNF40 at the damage sites is expected to induce H2Bub locally at these sites.…”

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confidence: 99%

“…The recent data suggested that the ATM-RNF20-RNF40-H2Bub axis functions independently and later, and is required for the actual DSB repair process. Collectively, the data call for a model of chromatin relaxation at DSB sites as a two-stage process consisting of a rapid, ATM-independent chromatin decondensation that facilitates the recruitment of sensors, and an ATM-dependent stage at the level of the 30-nm chromatin fiber, which is mediated by ATMs substrate, RNF20-RNF40 [90]. …”

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

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

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“…Monoubiquitylation of H2A and H2B is thought to interfere with chromatin compaction (as observed in transcriptional regulation) and thereby to facilitate assembly of the repair machinery at foci of DNA damage (Moyal et al . 2011), but the underlying mechanisms remain elusive.…”

Section: Regulation Of Dna Damage Repair and Dna Replication By Monoumentioning

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Protein monoubiquitylation: targets and diverse functions

Nakagawa

Nakayama

2015

Genes to Cells

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Ubiquitin is a 76‐amino acid protein whose conjugation to protein targets is a form of post‐translational modification. Protein ubiquitylation is characterized by the covalent attachment of the COOH‐terminal carboxyl group of ubiquitin to an amino group of the substrate protein. Given that the NH2‐terminal amino group is usually masked, internal lysine residues are most often targeted for ubiquitylation. Polyubiquitylation refers to the formation of a polyubiquitin chain on the substrate as a result of the ubiquitylation of conjugated ubiquitin. The structures of such polyubiquitin chains depend on the specific lysine residues of ubiquitin targeted for ubiquitylation. Most of the polyubiquitin chains other than those linked via lysine‐63 and methionine‐1 of ubiquitin are recognized by the proteasome and serve as a trigger for substrate degradation. In contrast, polyubiquitin chains linked via lysine‐63 and methionine‐1 serve as a binding platform for proteins that function in immune signal transduction or DNA repair. With the exception of a few targets such as histones, the functions of protein monoubiquitylation have remained less clear. However, recent proteomics analysis has shown that monoubiquitylation occurs more frequently than polyubiquitylation, and studies are beginning to provide insight into its biologically important functions. Here, we summarize recent findings on protein monoubiquitylation to provide an overview of the targets and molecular functions of this modification.

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