A Small Molecule Inhibitor of Polycomb Repressive Complex 1 Inhibits Ubiquitin Signaling at DNA Double-strand Breaks

Ismail, Ismail Hassan; McDonald, Darin; Strickfaden, Hilmar; Xu, Zhaochun; Hendzel, Michael J.

doi:10.1074/jbc.m113.461699

Cited by 83 publications

(72 citation statements)

References 31 publications

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“…Notably, beyond its key role in Polycomb-mediated gene repression, the PRC1 ubiquitin ligase catalytic subunit BMI-1 rapidly relocalizes to IRIF where it regulates DSB repair via ubiquitylation of H2A and H2AX (44, 45). In line with the results of Ismail et al (46), treating cells with the BMI-1 inhibitor PRT4165 markedly delayed IRIF resolution ( P ≤ 0.001, Fig. 6E–F).…”

Section: Resultssupporting

confidence: 91%

Linking Cancer Metabolism to DNA Repair and Accelerated Senescence

Efimova

Takahashi

Shamsi

et al. 2016

Molecular Cancer Research

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Conventional wisdom ascribes metabolic reprogramming in cancer to meeting increased demands for intermediates to support rapid proliferation. Prior models have proposed benefits toward cell survival, immortality and stress resistance while the recent discovery of oncometabolites has shifted attention to chromatin targets affecting gene expression. To explore further effects of cancer metabolism and epigenetic deregulation, DNA repair kinetics were examined in cells treated with metabolic intermediates, oncometabolites and/or metabolic inhibitors by tracking resolution of double strand breaks (DSBs) in irradiated MCF7 breast cancer cells. Disrupting cancer metabolism revealed roles for both glycolysis and glutaminolysis in promoting DSB repair and preventing accelerated senescence after irradiation. Targeting pathways common to glycolysis and glutaminolysis uncovered opposing effects of the hexosamine biosynthetic pathway (HBP) and tricarboxylic acid (TCA) cycle. Treating cells with the HBP metabolite N-acetylglucosamine (GlcNAc) or augmenting protein O-GlcNAcylation with small molecules or RNAi targeting O-GlcNAcase enhanced DSB repair, while targeting O-GlcNAc transferase reversed GlcNAc’s effects. Opposing the HBP, TCA metabolites including α-ketoglutarate blocked DSB resolution. Strikingly, DNA repair could be restored by the oncometabolite 2-hydroxyglutarate (2-HG). Targeting downstream effectors of histone methylation and demethylation implicated the PRC1/2 polycomb complexes as the ultimate targets for metabolic regulation, reflecting known roles for Polycomb group proteins in non-homologous end-joining (NHEJ) DSB repair. Our findings that epigenetic effects of cancer metabolic reprogramming may promote DNA repair provide a molecular mechanism by which deregulation of metabolism may not only support cell growth but also maintain cell immortality, drive therapeutic resistance and promote genomic instability.

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Section: Resultssupporting

confidence: 91%

Linking Cancer Metabolism to DNA Repair and Accelerated Senescence

Efimova

Takahashi

Shamsi

et al. 2016

Molecular Cancer Research

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“…S4 A), further supporting a role for ZRF1 in UV-mediated DNA repair. We next addressed the association of ZRF1 with DNA lesions in the presence of the RING1B inhibitor PRT4165 (Ismail et al, 2013). Under control conditions, we observed ZRF1 at DNA lesions ( Fig.…”

Section: Zrf1 Tethers To the H2a-ubiquitin Mark During Uv-triggered Dmentioning

confidence: 95%

ZRF1 mediates remodeling of E3 ligases at DNA lesion sites during nucleotide excision repair

Gracheva

Chitale

Wilhelm

et al. 2016

Journal of Cell Biology

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“…The DNA damage response signaling from a DSB triggers a sequence of ubiquitylation events that ultimately cause checkpoint activation [4,5]. The ubiquitylation of H2A at DSBs is very well studied, and takes place on lysines 13-15 [6] and lysine 119 [58][59][60]. These modifications are brought about by RNF8, RNF168, and the PRC1 complex ( DSBs (Fig.…”

Section: Does Zrf1-mediated On-site Remodeling Occur At Dsbs and Durimentioning

confidence: 99%

On‐site remodeling at chromatin: How multiprotein complexes are rebuilt during DNA repair and transcriptional activation

Papadopoulou

Richly

2016

BioEssays

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In this review, we discuss a novel on-site remodeling function that is mediated by the H2A-ubiquitin binding protein ZRF1. ZRF1 facilitates the remodeling of multiprotein complexes at chromatin and lies at the heart of signaling processes that occur at DNA damage sites and during transcriptional activation. In nucleotide excision repair ZRF1 remodels E3 ubiquitin ligase complexes at the damage site. During embryonic stem cell differentiation, it contributes to retinoic acid-mediated gene activation by altering the subunit composition of the Mediator complex. We postulate that ZRF1 operates in conjunction with cellular remodeling machines and suggest that on-site remodeling might be a hallmark of many chromatin-associated signaling pathways. We discuss yet unexplored functions of ZRF1-mediated remodeling in replication and double strand break repair. In conclusion, we postulate that on-site remodeling of multiprotein complexes is essential for the timing of chromatin signaling processes.

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A Small Molecule Inhibitor of Polycomb Repressive Complex 1 Inhibits Ubiquitin Signaling at DNA Double-strand Breaks

Cited by 83 publications

References 31 publications

Linking Cancer Metabolism to DNA Repair and Accelerated Senescence

Linking Cancer Metabolism to DNA Repair and Accelerated Senescence

ZRF1 mediates remodeling of E3 ligases at DNA lesion sites during nucleotide excision repair

On‐site remodeling at chromatin: How multiprotein complexes are rebuilt during DNA repair and transcriptional activation

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