CHK2-mediated regulation of PARP1 in oxidative DNA damage response

Hsu, Pei-Ching; Gopinath, Rajaneesh Karimpurath; Hsueh, Yi-An; Shieh, Sheau‐Yann

doi:10.1038/s41388-018-0506-7

Cited by 20 publications

(31 citation statements)

References 56 publications

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“…ATM serine/threonine kinase (ATM), Checkpoint kinase 1 (Chk1), Checkpoint kinase 2 (Chk2), and p53 are known to play a pivotal role in the control of cell response to external damages, indeed, they are induced by free radicals and involved in apoptosis activation following DNA damage [45][46][47][48]. In order to elucidate the molecular pathways modulated by HT, using H 2 O 2 to mimic oxidative stress-induced injury (OSI) within a short period, we performed a western blot analysis of ATM, Chk1, Chk2, and p53 proteins (Figure 6).…”

Section: Ht Prevents Activation Of Key Dna Damage-associated Proteinsmentioning

confidence: 99%

Keratinocytes Migration Promotion, Proliferation Induction, and Free Radical Injury Prevention by 3-Hydroxytirosol

Abate

Citro

Pisanti

et al. 2021

IJMS

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3-hydroxytyrosol (HT) is the main phenolic compound found in olive oil with known antioxidant, anti-inflammatory, and antimicrobial properties in several dermatological conditions, both when taken in the form of olive oil or pure in cosmeceutical formulations. To date, its direct effect on the wound healing process and the molecular mechanisms involved have not yet been elucidated. Thus, in the present study, we aimed to explore its effects in vitro in epidermal keratinocyte cultures focusing on the molecular mechanism implied. HT was able to induce keratinocyte proliferation in the low micromolar range, increasing the expression of cyclin dependent kinases fundamental for cell cycle progression such as CDK2 and CDK6. Furthermore, it increased cell migration through the activation of tissue remodeling factors such as matrix metalloproteinase-9 (MMP-9) protein. Then, we evaluated whether HT also showed antioxidant activity at this concentration range, protecting from H2O2-induced cytotoxicity. The HT prevented the activation of ATM serine/threonine kinase (ATM), Checkpoint kinase 1 (Chk1), Checkpoint kinase 2 (Chk2), and p53, reducing the number of apoptotic cells. Our study highlighted novel pharmacological properties of HT, providing the first evidence of its capability to induce keratinocyte migration and proliferation required for healing processes and re-epithelialization.

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Section: Ht Prevents Activation Of Key Dna Damage-associated Proteinsmentioning

confidence: 99%

Keratinocytes Migration Promotion, Proliferation Induction, and Free Radical Injury Prevention by 3-Hydroxytirosol

Abate

Citro

Pisanti

et al. 2021

IJMS

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“…In addition to the domains involved in DNA-break recognition and catalytic activation, PARP1 contains a BRCT-like (BRCA1 C-terminus) domain where most of the auto-modification sites have been identified Tao et al, 2009) and which is implicated in mediating protein-protein interactions (Liu et al, 2011;Noren Hooten et al, 2011;Hsu et al, 2019) ADP-ribosylation of DNA ADP-ribosylation was long considered a protein modification exclusively. However, recent reports have independently shown that DNA-dependent PARPs can add ADPr covalently to DNA ends, at least in vitro (Talhaoui et al, 2016;Munnur and Ahel, 2017;Zarkovic et al, 2018).…”

Section: Domain Architecture and Activationmentioning

confidence: 99%

ADP-ribosylation: from molecular mechanisms to human disease

Hoch

Polo

2020

Genet. Mol. Biol.

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Post-translational modification of proteins by ADP-ribosylation, catalysed by poly (ADP-ribose) polymerases (PARPs) using NAD + as a substrate, plays central roles in DNA damage signalling and repair, modulates a range of cellular signalling cascades and initiates programmed cell death by parthanatos. Here, we present mechanistic aspects of ADP-ribose modification, PARP activation and the cellular functions of ADP-ribose signalling, and discuss how this knowledge is uncovering therapeutic avenues for the treatment of increasingly prevalent human diseases such as cancer, ischaemic damage and neurodegeneration.The PARP1 active site is formed between the catalytic domain (ART domain) and the helical domain (HD) Figure 1 -Schematic mechanism of ADP ribosylation reaction and the catalytic domain of DNA-dependant PARPs. A) A simplified overview of the (ADP)-ribosylation reactions catalysed by PARPs. The final products depend on the acceptor residue acting as a nucleophile (Nu, in blue). PARP1 active-site residues interacting with the ribose-nicotinamide moiety of NAD + are illustrated in orange. B) The NAD + (modelled based on the human PARP1 bound to benzamide adenine dinucleotide [PDB: 6BHV], carbon atoms in yellow) in an extended conformation, bound to the catalytic domain of human PARP1 (ART in cartoon, orange, [PDB: 6BHV]). The residues involved in the catalysis are presented as sticks. C) Superposed cartoon view of human PARP-1 ART domain (orange, [PDB: 6BHV]), PARP1 (light blue, [PDB: 5WS1]) and PARP2 (green, [PDB: 3KJD]) showing the structure of the entire catalytic domains (ART and HD). The modelled NAD + (in yellow) denotes the donor site, while a molecule of ADP (modelled by superimposing the structures of chicken PARP1 [PDB: 1A26] to the human PARP1 [PDB: 3KJD]) indicates the acceptor site. Donor loop (D-loop) and acceptor loop are labelled. D) Surface representation of human PARP1 [PDB: 3KJD] with NAD + modelled into the active site. The ribose group to be attacked is exposed to the solvent. ADP-ribose mechanisms and disease 3 ADP-ribose mechanisms and disease 13

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“…Thus, agents that weaken the antioxidant systems or promote generation of ROS can induce oxidative DNA damage selectively in cancer cells [24][25][26][27]. PARP1/2 are required for the repair of oxidative DNA lesions [28][29][30] and it has been shown that PARP inhibition sensitizes cells to oxidative stress [31][32][33], raising the possibility of using PARPis in combination with prooxidative agents to yield cancer-specific synergistic lethality. The natural compound alantolactone (ATL) increases cellular ROS levels by inhibiting the thioredoxin reductase (TrxR) [34][35][36][37].…”

Section: Introductionmentioning

confidence: 99%

Synergistic lethality between PARP-trapping and alantolactone-induced oxidative DNA damage in homologous recombination-proficient cancer cells

et al. 2020

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PARP1 and PARP2 play critical roles in regulating DNA repair and PARP inhibitors have been approved for the treatment of BRCA1/2-mutated ovarian and breast cancers. It has long been known that PARP inhibition sensitizes cancer cells to DNAdamaging cytotoxic agents independent of BRCA status, however, clinical use of PARP inhibitors in combination with DNAdamaging chemotherapy is limited by the more-than-additive cytotoxicity. The natural compound alantolactone (ATL) inhibits the thioredoxin reductase to induce ROS accumulation and oxidative DNA damage selectively in cancer cells. Here, we showed that nontoxic doses of ATL markedly synergized with the PARP inhibitor olaparib to result in synthetic lethality irrespective of homologous recombination status. Synergistic cytotoxicity was seen in cancer but not noncancerous cells and was reduced by the ROS inhibitor NAC or knockdown of OGG1, demonstrating that the cytotoxicity resulted from the repair of ATL-induced oxidative DNA damage. PARP1 knockdown suppressed the synergistic lethality and olaparib was much more toxic than veliparib when combined with ATL, suggesting PARP-trapping as the primary inducer of cytotoxicity. Consistently, combined use of ATL and olaparib caused intense signs of replication stress and formation of double strand DNA breaks, leading to S and G 2 arrest followed by apoptosis. In vivo, the combination effectively induced regression of tumor xenografts, while either agent alone had no effect. Hence, PARP trapping combined with specific pro-oxidative agents may provide safe and effective ways to broaden the therapeutic potential of PARP inhibitors.

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CHK2-mediated regulation of PARP1 in oxidative DNA damage response

Cited by 20 publications

References 56 publications

Keratinocytes Migration Promotion, Proliferation Induction, and Free Radical Injury Prevention by 3-Hydroxytirosol

Keratinocytes Migration Promotion, Proliferation Induction, and Free Radical Injury Prevention by 3-Hydroxytirosol

ADP-ribosylation: from molecular mechanisms to human disease

Synergistic lethality between PARP-trapping and alantolactone-induced oxidative DNA damage in homologous recombination-proficient cancer cells

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