The DNA Damage Checkpoint Response Requires Histone H2B Ubiquitination by Rad6-Bre1 and H3 Methylation by Dot1

Giannattasio, Michele; Lazzaro, Federico; Plevani, Paolo; Muzi-Falconi, Marco

doi:10.1074/jbc.m414453200

Cited by 269 publications

(275 citation statements)

References 57 publications

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“…Here, too, the DDR relies on recruitment of existing players in the chromatin organization arena [32][33][34][75][76][77][78][79][81][82][83][84][85]. H2B monoubiquitylation was previously implicated in the DDR in the budding yeast [86][87][88]. Three recent studies -by Nakamura et al [89], Moyal et al [90] and Chernikova et al [91] -demonstrated the importance of this process in the DSB response in human cells and provided further insight into its mechanistic aspects: H2Bub was found to be induced by DSBs, most likely at DSB sites, and required for timely repair of this lesion.…”

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

confidence: 99%

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

confidence: 99%

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

et al. 2011

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“…Budding yeast Dot1 has been shown to function in the regulation of the meiotic checkpoint (23) and the DNA damage checkpoint (24,25). Trypanosoma brucei DOT1A and DOT1B, which mediate di-and trimethylation of H3K76, a homologue of H3K79 in other organisms, are required for normal proliferation and differentiation, respectively (26).…”

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Deficiency of H3K79 Histone Methyltransferase Dot1-like Protein (DOT1L) Inhibits Cell Proliferation

Kim

Park

et al. 2012

Journal of Biological Chemistry

117

111

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“…In association with Bre1 and Lge1, Rad6 also monoubiquitinates H2B (25,34,45), which plays a critical role in both the initiation and elongation of RNA polymerase (Pol) II transcription (6,19,27,48). While H2B ubiquitination is required under normal cellular conditions for transcription of certain genes, maintenance of H2B ubiquitination levels is also critical for the transcriptional and cell cycle response to DNA damage (15).…”

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Role of Doa1 in the Saccharomyces cerevisiae DNA Damage Response

Lis

Romesberg

2006

Molecular and Cellular Biology

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The cellular response to DNA damage requires not only direct repair of the damage but also changes in the DNA replication machinery, chromatin, and transcription that facilitate survival. Here, we describe Saccharomyces cerevisiae Doa1, which helps to control the damage response by channeling ubiquitin from the proteosomal degradation pathway into pathways that mediate altered DNA replication and chromatin modification. DOA1 interacts with genes involved in PCNA ubiquitination, including RAD6, RAD18, RAD5, UBC13, and MMS2, as well as genes involved in histone H2B ubiquitination or deubiquitination, including RAD6, BRE1, LGE1, CDC73, UBP8, UBP10, and HTB2. In the absence of DOA1, damage-induced ubiquitination of PCNA does not occur. In addition, the level of ubiquitinated H2B is decreased under normal conditions and completely absent in the presence of DNA damage. In the case of PCNA, the defect associated with the doa1⌬ mutant is alleviated by overexpression of ubiquitin, but in the case of H2B, it is not. The data suggest that Doa1 is the major source of ubiquitin for the DNA damage response and that Doa1 also plays an additional essential and more specific role in the monoubiquitination of histone H2B.

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The DNA Damage Checkpoint Response Requires Histone H2B Ubiquitination by Rad6-Bre1 and H3 Methylation by Dot1

Cited by 269 publications

References 57 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

Deficiency of H3K79 Histone Methyltransferase Dot1-like Protein (DOT1L) Inhibits Cell Proliferation

Role of Doa1 in the Saccharomyces cerevisiae DNA Damage Response

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