RNF8 Transduces the DNA-Damage Signal via Histone Ubiquitylation and Checkpoint Protein Assembly

Huen, Michael S.Y.; Grant, Robert A.; Manke, Isaac A.; Minn, Kay; Yu, Xiaochun; Yaffe, Michael B.; Chen, Junjie

doi:10.1016/j.cell.2007.09.041

Cited by 925 publications

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“…Furthermore, the expression of polyadenylated canonical histone mRNAs may be important for cells experiencing DNA damage. The polyubiquitination and exchange of core histones following DNA damage is essential for the cellular DNA damage response (Wang et al, 2006;Huen et al, 2007;Mailand et al, 2007). Therefore, newly synthesized histone proteins (that is, from the polyadenylated histone mRNAs) may help maintain proper chromatin structure subsequent to DNA repair.…”

Section: Discussionmentioning

confidence: 99%

Induced G1 cell-cycle arrest controls replication-dependent histone mRNA 3′ end processing through p21, NPAT and CDK9

Pirngruber

Johnsen

2010

Oncogene

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Proper cell cycle-dependent expression of replicationdependent histones is essential for packaging of DNA into chromatin during replication. We previously showed that cyclin-dependent kinase-9 (CDK9) controls histone H2B monoubiquitination (H2Bub1) to direct the recruitment of specific mRNA 3 0 end processing proteins to replicationdependent histone genes and promote proper pre-mRNA 3 0 end processing. We now show that p53 decreases the expression of the histone-specific transcriptional regulator Nuclear Protein, Ataxia-Telangiectasia Locus (NPAT) by inducing a G1 cell-cycle arrest, thereby affecting E2F-dependent transcription of the NPAT gene. Furthermore, NPAT is essential for histone mRNA 3 0 end processing and recruits CDK9 to replication-dependent histone genes. Reduced NPAT expression following p53 activation or small interfering RNA knockdown decreases CDK9 recruitment and replication-dependent histone gene transcription but increases the polyadenylation of remaining histone mRNAs. Thus, we present evidence that the induction of a G1 cell-cycle arrest (for example, following p53 accumulation) alters histone mRNA 3 0 end processing and uncover the first mechanism of a regulated switch in the mode of pre-mRNA 3 0 end processing during a normal cellular process, which may be altered during tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Induced G1 cell-cycle arrest controls replication-dependent histone mRNA 3′ end processing through p21, NPAT and CDK9

Pirngruber

Johnsen

2010

Oncogene

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“…ATM activation has been extensively studied in relation to its activation by DSBs in the DNA damage response (DDR). There has been enormous progress on the delineation of the DDR pathway regulated by the apical ATM and ATR kinases and the role of ubiquitination reactions in both the assembly and transduction of their cellular responses [Harper and Elledge, 2007;Huen et al, 2007;Yan and Jetten, 2008]. The ATM pathway is activated in response to DSBs, while ATR is activated largely by the generation of ssDNA generated by stalling of replication forks in a process involving Replication protein A (RPA) and ATRIP [Cimprich and Cortez, 2008;Flynn and Zou, 2011].…”

Section: Degradation Of P12 and The Conversion Of Pol D4 To Pol D3 Inmentioning

confidence: 99%

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

Lee

Zhang

Lin

et al. 2012

Environ and Mol Mutagen

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The p12 subunit of polymerase delta (Pol d) is degraded in response to DNA damage induced by UV, alkylating agents, oxidative, and replication stresses. This leads to the conversion of the Pol d4 holoenzyme to the heterotrimer, Pol d3. We review studies that establish that Pol d3 formation is an event that could have a major impact on cellular processes in genomic surveillance, DNA replication, and DNA repair. p12 degradation is dependent on the apical ataxia telangiectasia and Rad3 related (ATR) kinase and is mediated by the ubiquitin-proteasome system. Pol d3 exhibits properties of an ''antimutator'' polymerase, suggesting that it could contribute to an increased surveillance against mutagenesis, for example, when Pol d carries out bypass synthesis past small base lesions that engage in spurious base pairing. Chromatin immunoprecipitation analysis and examination of the spatiotemporal recruitment of Pol d to sites of DNA damage show that Pol d3 is the primary form of Pol d associated with cyclobutane pyrimidine dimer lesions and therefore should be considered as the operative form of Pol d engaged in DNA repair. We propose a model for the switching of Pol d with translesion polymerases, incorporating the salient features of the recently determined structure of monoubiquitinated proliferating cell nuclear antigen and emphasizing the role of Pol d3. Because of the critical role of Pol d activity in DNA replication and repair, the formation of Pol d3 in response to DNA damage opens the prospect that pleiotropic effects may ensue. This opens the horizons for future exploration of how this novel response to DNA damage contributes to genomic stability. Environ. Mol. Mutagen. 53:683-698, 2012. V V C 2012 Wiley Periodicals, Inc.

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“…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]. Interestingly, unlike with H2Bub, the H2A ubiquitin ligases that function in the gene regulation context [116] were not implicated in DNA damage-induced H2A monoubiquitylation.…”

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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RNF8 Transduces the DNA-Damage Signal via Histone Ubiquitylation and Checkpoint Protein Assembly

Cited by 925 publications

References 47 publications

Induced G1 cell-cycle arrest controls replication-dependent histone mRNA 3′ end processing through p21, NPAT and CDK9

Induced G1 cell-cycle arrest controls replication-dependent histone mRNA 3′ end processing through p21, NPAT and CDK9

Regulation of human DNA polymerase delta in the cellular responses to DNA damage

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

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