Emerging roles of eraser enzymes in the dynamic control of protein ADP-ribosylation

O’Sullivan, Julia; Ferreira, Maria Tedim; Gagné, Jean-Philippe; Sharma, Ajit; Hendzel, Michael J.; Masson, Jean‐Yves; Poirier, Guy G.

doi:10.1038/s41467-019-08859-x

Cited by 128 publications

(131 citation statements)

References 148 publications

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“…Retention of KDM5A-F8 was transient, with the maximum intensity of recruitment occurring within the first minute post-damage induction followed by a steady decline in localization at damage sites. These recruitment dynamics were reminiscent of the short lifespan of PAR chains, which are rapidly removed by Poly ADP-ribose hydrolase (PARG) (Alvarez- Gonzalez and Althaus, 1989;Kassab et al, 2020;O'Sullivan et al, 2019). In sum, these results map the PAR interaction domain of KDM5A within the amino acids 1491-1610 and show that this region is sufficient for localization to damage sites, supporting its identification as a PAR binding domain within KDM5A.…”

Section: Kdm5a Directly Binds Par Chains In Vitromentioning

confidence: 74%

Poly(ADP-ribose)-binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions

Kumbhar

Perren

Gong

et al. 2020

Preprint

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The histone demethylase KDM5A removes histone H3 lysine 4 methylation, which is involved in transcription and DNA damage responses (DDR). While DDR functions of KDM5A have been identified, how KDM5A recognizes DNA lesion sites within chromatin is unknown. Here, we identify two factors that act upstream of KDM5A to promote its association with DNA damage sites. We have identified a non-canonical poly(ADP-ribose), (PAR), binding region unique to KDM5A. Loss of the PAR-binding region or treatment with PAR polymerase (PARP) inhibitors (PARPi) blocks KDM5A-PAR interactions and DNA repair functions of KDM5A. The histone variant macroH2A1.2 is also specifically required for KDM5A recruitment and functions at DNA damage sites, including homology-directed repair of DNA double-strand breaks and repression of transcription at DNA breaks. Overall, this work reveals the importance of PAR-binding and macroH2A1.2 in KDM5A recognition of damage sites that drive transcriptional and repair activities at DNA breaks within chromatin that are essential for maintaining genome integrity.SummaryThe histone demethylase KDM5A demethylates H3K4 to promote repair and transcriptional responses at DNA breaks. We identified poly(ADP-ribose)-binding and macroH2A1.2 as modulators of KDM5A association with DNA damage sites, revealing how KDM5A engages DNA breaks within chromatin.

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Section: Kdm5a Directly Binds Par Chains In Vitromentioning

confidence: 74%

Poly(ADP-ribose)-binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions

Kumbhar

Perren

Gong

et al. 2020

Preprint

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“…Accumulation of PAR and loss of NAD + and ATP can lead to severe metabolic dysfunction and eventual cell death. Thus, the balance between ADP-ribose synthesis (i.e., PAR writers) and degradation (i.e., PAR erasers) is critical for the coordination of various cellular response pathways for survival [54].…”

Section: Harnessing the Power Of Par And Parg Inhibition For Cancer Tmentioning

confidence: 99%

Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy

Singh

Pay

Bhandare

et al. 2020

Cancers

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Poly-(ADP-ribose) polymerase 1 (PARP1) is commonly known for its vital role in DNA damage response and repair. However, its enzymatic activity has been linked to a plethora of physiological and pathophysiological transactions ranging from cellular proliferation, survival and death. For instance, malignancies with BRCA1/2 mutations heavily rely on PARP activity for survival. Thus, the use of PARP inhibitors is a well-established intervention in these types of tumors. However, recent studies indicate that the therapeutic potential of attenuating PARP1 activity in recalcitrant tumors, especially where PARP1 is aberrantly overexpressed and hyperactivated, may extend its therapeutic utility in wider cancer types beyond BRCA-deficiency. Here, we discuss treatment strategies to expand the tumor-selective therapeutic application of PARP inhibitors and novel approaches with predictive biomarkers to perturb NAD+ levels and hyperPARylation that inactivate PARP in recalcitrant tumors. We also provide an overview of genetic alterations that transform non-BRCA mutant cancers to a state of “BRCAness” as potential biomarkers for synthetic lethality with PARP inhibitors. Finally, we discuss a paradigm shift for the use of novel PARP inhibitors outside of cancer treatment, where it has the potential to rescue normal cells from severe oxidative damage during ischemia-reperfusion injury induced by surgery and radiotherapy.

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“…ADPr is dynamically regulated by the activity of specialised ADPribosyl hydrolases, which reverse the modification once the cellular response has been achieved ( Fig. 1) [5,156,157]. Two evolutionary unrelated protein families are known to support this function: DraG-like ADP-ribosyl-acceptor hydrolases (ARHs) and macrodomain-containing enzymes.…”

Section: Adp-ribosyl Hydrolasesmentioning

confidence: 99%

“…DraG is a Mg 2+ -dependent arginine-hydrolase known to counteract the activity of the ART endotoxin DraT in the photosynthetic bacterium Rhodospirillum rubrum [168] (detailed in Section 4.2). The human genome encodes three DraG-related ARHs (ARH1, ARH2, and ARH3), which play roles as regulators of cellular stresses [157,161,163,164]. Similarly to bacterial DraGs, ARH1 reverses arginine ADPr operated by mammalian ARTCs as well as bacterial toxins [162,167] In this regards, ARH1-deficient mice, exhibited enhanced sensitivity to Cholera toxin [169,170], thus suggesting that modification of cellular substrates performed by bARTs can be reverted by mammalian hydrolases [162].…”

Section: Adp-ribosyl Hydrolasesmentioning

confidence: 99%

Targeting ADP-ribosylation as an antimicrobial strategy

Catara

Corteggio

Valente

et al. 2019

Biochemical Pharmacology

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A B S T R A C T ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules controlling major biological processes as diverse as DNA damage repair, transcriptional regulation, intracellular transport, immune and stress responses, cell survival and proliferation. Furthermore, enzymatic reactions of ADPr are central in the pathogenesis of many human diseases, including infectious conditions. By providing a review of ADPr signalling in bacterial systems, we highlight the relevance of this chemical modification in the pathogenesis of human diseases depending on host-pathogen interactions. The post-antibiotic era has raised the need to find alternative approaches to antibiotic administration, as major pathogens becoming resistant to antibiotics. An in-depth understanding of ADPr reactions provides the rationale for designing novel antimicrobial strategies for treatment of infectious diseases. In addition, the understanding of mechanisms of ADPr by bacterial virulence factors offers important hints to improve our knowledge on cellular processes regulated by eukaryotic homologous enzymes, which are often involved in the pathogenesis of human diseases.T large number of worldwide spread diseases, affecting humans, insects and plants [31,[56][57][58], with a great impact on human health. In addition, infectious diseases strongly affect the world economy in terms of costs for the human health as well as food and agricultural economic losses [59]. The use of antibiotics to counteract the pathogen infections has represented the therapeutic strategy of choice in the last century, however the emergence of antibiotic resistance strains represents the major challenge of the 21st century [60][61][62]. Targeting bacterial pathogenic mechanisms by disarming pathogens of virulence factors, for instance by inhibiting the enzymatic activity of bART, represents a valid alternative intervention strategy to overcome antibiotic resistance [63][64][65][66]. In addition, because of the conservation of ADPr systems throughout the evolution, the understanding of bacterial pathogenic mechanisms may contribute to unveil novel and conserved cellular processes regulated by ADPr in high organisms [34,45,67,68]. The dysregulation of such processes can be either cause of human diseases or be target of therapeutic intervention [39,[69][70][71].Herein, we will provide a summary of bacterial ADPr systems describing their pathogenic mechanisms and highlighting the similarities with ADPr systems in mammals as well. Further, we discuss the potential of targeting ADPr for therapeutic strategies of infection diseases. ADP-ribosylation in pathophysiologyADPr was originally described in the 60s; two independent studies reported the identification of a new polymer, poly(ADP-ribose) (PAR) synthesised from NAD + in vertebrate cells [72] and, simultaneously, the finding that bacterial DTX activity from C. diphteriae is dependent on NAD + content [73]. In the following decades, research in the field has expanded the involvement of ADPr ...

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Emerging roles of eraser enzymes in the dynamic control of protein ADP-ribosylation

Cited by 128 publications

References 148 publications

Poly(ADP-ribose)-binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions

Poly(ADP-ribose)-binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions

Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy

Targeting ADP-ribosylation as an antimicrobial strategy

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