The RNA Response to DNA Damage

Giono, Luciana E.; Moreno, Nicolás Nieto; Botto, Adrián E. Cambindo; Dujardin, Geneviève; Muñoz, Manuel J.; Kornblihtt, Alberto R.

doi:10.1016/j.jmb.2016.03.004

Cited by 47 publications

(30 citation statements)

References 165 publications

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“…Expression of SLBP(RL97/99AA) was associated with a significant fold increase of total H2AFX mRNA in the light polyribosome fraction, but not in the heavy polyribosome fraction (Figure 5E). DNA damage induces a genome-wide downregulation in translation initiation (reviewed in Giono et al, 2016). Therefore, the increase of total H2AFX mRNA in the light polyribosome fraction occurs against a backdrop of overall reduction in cellular protein synthesis, accounting for the absence of an increase of total H2AFX mRNA in the heavy polyribosome fraction.…”

Section: Resultsmentioning

confidence: 99%

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

et al. 2016

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Summary SLBP (stem-loop binding protein) is a highly conserved factor necessary for the processing, translation, and degradation of H2AFX and canonical histone mRNAs. We identified the F-box protein cyclin F, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the G2 ubiquitin ligase for SLBP. SLBP interacts with cyclin F via an atypical CY motif, and mutation of this motif prevents SLBP degradation in G2. Expression of an SLBP stable mutant results in increased loading of H2AFX mRNA onto polyribosomes, resulting in increased expression of H2A.X (encoded by H2AFX). Upon genotoxic stress in G2, high levels of H2A.X lead to persistent γH2A.X signaling, high levels of H2A.X phosphorylated on Tyr142, high levels of p53, and induction of apoptosis. We propose that cyclin F co-evolved with the appearance of stem-loops in vertebrate H2AFX mRNA to mediate SLBP degradation, thereby limiting H2A.X synthesis and cell death upon genotoxic stress.

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Section: Resultsmentioning

confidence: 99%

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

et al. 2016

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“…Defective DDR can lead to genomic instability underlying many diseases, including hematological disorders and cancer (Jackson and Bartek, 2009). Importantly, it is widely accepted that cells need to shut down Pol II transcription in response to ultraviolet light (UV)-induced bulky DNA lesions and other types of DNA damage, which can facilitate the repair and limit the production of abnormal transcripts (Giono et al, 2016). While transcription can be inhibited transiently at initiation and elongation stages (Awwad et al, 2017;Rockx et al, 2000;Williamson et al, 2017), or irreversibly through degradation of stalled Pol II (Wilson et al, 2013), it is eventually restored once the damage is corrected.…”

Section: Introductionmentioning

confidence: 99%

P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress

Бугай

Quaresma

Friedel

et al. 2018

Preprint

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Cellular DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill-defined. Given the centrality of RNA polymerase II (Pol II) promoter-proximal pause release in transcriptional control, we evaluated its importance in DDR. Here we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates Pol II elongation and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb). This is mediated by genotoxic stressenhanced binding of RBM7 to 7SK snRNA (7SK), the scaffold of the 7SK small nuclear ribonucleoprotein (7SK snRNP) which inhibits P-TEFb. In turn, P-TEFb relocates from 7SK snRNP to chromatin to induce transcription of short units including key DDR genes and multiple classes of noncoding RNAs. Critically, interfering with RBM7 or P-TEFb provokes cellular hypersensitivity to DNA damage-inducing agents through activation of apoptotic program. By alleviating the inhibition of P-TEFb, RBM7 thus facilitates Pol II elongation to enable a pro-survival transcriptional response that is crucial for cell fate upon genotoxic insult. Our work uncovers a new paradigm in stress-dependent control of Pol II pause release, and offers the promise for designing novel anti-cancer interventions using RBM7 and P-TEFb antagonists in combination with DNA-damaging chemotherapeutics.

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“…There are a number of genes whose alternative splicing is altered under genotoxic stress [202,203]. One of the more extensively studied of these genes is MDM2 (Mouse double minute 2) [202,204].…”

Section: Pdip38 Responds To Genotoxic and Transcriptional Stress By Tmentioning

confidence: 99%

Regulation and Modulation of Human DNA Polymerase δ Activity and Function

Lee

Wang

Zhang

et al. 2017

Preprint

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This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol δ binding proteins, PDIP46 and PDIP38, both of which are multi-functional proteins. PDIP46 is a novel activator of Pol δ4, and the impact of this function is discussed in relation to its potential roles in DNA replication. Several new models for the roles of Pol δ3 and Pol δ4 in leading and lagging strand DNA synthesis that integrate a role for PDIP46 are presented. PDIP38 has multiple cellular localizations including the mitochondria, the splicesosomes and the nucleus. It has been implicated in a number of cellular functions, including the regulation of specialized DNA polymerases, mitosis, the DNA damage response, Mdm2 alternative splicing and the regulation of the Nox4 NADPH oxidase.

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The RNA Response to DNA Damage

Cited by 47 publications

References 165 publications

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress

Regulation and Modulation of Human DNA Polymerase δ Activity and Function

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The RNA Response to DNA Damage

Cited by 47 publications

References 165 publications

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

Cyclin F-Mediated Degradation of SLBP Limits H2A.X Accumulation and Apoptosis upon Genotoxic Stress in G2

P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress

Regulation and Modulation of Human DNA Polymerase &delta; Activity and Function

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Regulation and Modulation of Human DNA Polymerase δ Activity and Function