Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical–induced DNA damage

Chiang, Shih‐Chieh; Meagher, Martin; Kassouf, Nick; Hafezparast, Majid; McKinnon, Peter J.; Haywood, Rachel; El‐Khamisy, Sherif F.

doi:10.1126/sciadv.1602506

Cited by 49 publications

(57 citation statements)

References 75 publications

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“…This result was supported by our further observation that mtDNA 8-OHdG positively correlated with coronary stenosis severity, as determined by the number of diseased vessels and modified Gensini scores. Indeed, functional studies have suggested that mtDNA oxidative damage under diabetic conditions may trigger a series of pathological events including abnormal mitochondrial gene transcription, uncontrolled oxidative stress, and endothelial dysfunction [12,53], all of which contribute to plaque progression and rupture [54]. In vitro, hyperglycemia may also induce the interaction of mtDNA oxidative damage with inflammatory cytokine release, causing apoptosis of monocytes, T2DM-related endothelial dysfunction, and plaque instability [48].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial 8-hydroxy-2′-deoxyguanosine and coronary artery disease in patients with type 2 diabetes mellitus

Wang

Cui

Liu

et al. 2020

Cardiovasc Diabetol

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Background: Little is known about whether mitochondria 8-hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of mitochondrial DNA (mtDNA) oxidative damage, contributes to the development of coronary artery disease (CAD) in diabetic patients. Here, we explored the associations of mtDNA 8-OHdG in leukocytes with obstructive CAD, coronary stenosis severity, cardiovascular biomarkers, and 1-year adverse outcomes after coronary revascularization in patients with type 2 diabetes mellitus (T2DM). Methods: In a total of 1920 consecutive patients with T2DM who underwent coronary angiography due to symptoms of angina or angina equivalents, the presence of obstructive CAD, the number of diseased vessels with ≥ 50% stenosis, and modified Gensini score were cross-sectionally evaluated; the level of mtDNA 8-OHdG was quantified by quantitative PCR. Then, 701 of 1920 diabetic patients who further received coronary revascularization completed 1-year prospective follow-up to document major adverse cardiovascular and cerebral events (MACCEs). In vitro experiments were also performed to observe the effects of mtDNA oxidative damage in high glucose-cultured human umbilical vein endothelial cells (HUVECs). Results: Cross-sectionally, greater mtDNA 8-OHdG was associated with increased odds of obstructive CAD (odds ratio [OR] 1.38, 95% CI confidence interval 1.24-1.52), higher degree of coronary stenosis (number of diseased vessels: OR 1.29, 95% CI 1.19-1.41; modified Gensini scores: OR 1.28, 95% CI 1.18-1.39), and higher levels of C-reactive protein (β 0.18, 95% CI 0.06-0.31) after adjusting for confounders. Sensitivity analyses using propensity score matching yielded similar results. Stratification by smoking status showed that the association between mtDNA 8-OHdG and obstructive CAD was most evident in current smokers (P interation < 0.01). Prospectively, the adjusted hazards ratio per 1-SD increase in mtDNA 8-OHdG was 1.59 (95% CI 1.33-1.90) for predicting 1-year MACCEs after revascularization. In HUVECs, exposure to antimycin A, an inducer for mtDNA oxidative damage, led to adverse alterations in markers of mitochondrial and endothelia function. Conclusion: Greater mtDNA 8-OHdG in leukocytes may serve as an independent risk factor for CAD in patients with T2DM.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial 8-hydroxy-2′-deoxyguanosine and coronary artery disease in patients with type 2 diabetes mellitus

Wang

Cui

Liu

et al. 2020

Cardiovasc Diabetol

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“…Clones were then tested for TEX264-SSH or SPRTN-SHP*-SSH expression upon induction with 1-1.2 µg/mL Doxycycline by immunoblotting. Flp-In T-Rex-293 cells expressing miRNAs targetting TDP1 were generated as previously described 80 .…”

Section: Methodsmentioning

confidence: 99%

TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

et al. 2020

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Eukaryotic topoisomerase 1 (TOP1) regulates DNA topology to ensure efficient DNA replication and transcription. TOP1 is also a major driver of endogenous genome instability, particularly when its catalytic intermediate-a covalent TOP1-DNA adduct known as a TOP1 cleavage complex (TOP1cc)-is stabilised. TOP1ccs are highly cytotoxic and a failure to resolve them underlies the pathology of neurological disorders but is also exploited in cancer therapy where TOP1ccs are the target of widely used frontline anti-cancer drugs. A critical enzyme for TOP1cc resolution is the tyrosyl-DNA phosphodiesterase (TDP1), which hydrolyses the bond that links a tyrosine in the active site of TOP1 to a 3' phosphate group on a single-stranded (ss)DNA break. However, TDP1 can only process small peptide fragments from ssDNA ends, raising the question of how the~90 kDa TOP1 protein is processed upstream of TDP1. Here we find that TEX264 fulfils this role by forming a complex with the p97 ATPase and the SPRTN metalloprotease. We show that TEX264 recognises both unmodified and SUMO1-modifed TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN. TEX264 localises to the nuclear periphery, associates with DNA replication forks, and counteracts TOP1ccs during DNA replication. Altogether, our study elucidates the existence of a specialised repair complex required for upstream proteolysis of TOP1ccs and their subsequent resolution.

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“…If TDP1 reacts more rapidly with a nucleic acid -guanine radical than DMPO, then O 2 y− would be expected to react instead with DMPO. The effect of TDP1 in a cell system, was higher levels of carbon adducts but without the liberation of a peroxyl radical, in TDP1-deficient compared to wild type cells [31]. This, again, would be consistent with the relative hypoxia of cells compared to DNA-melanin in vitro.…”

Section: Discussionmentioning

confidence: 59%

UVA-induced carbon-centred radicals in lightly pigmented cells detected using ESR spectroscopy

Kassouf

Kay

Volkov

et al. 2018

Free Radical Biology and Medicine

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Mitochondrial protein-linked DNA breaks perturb mitochondrial gene transcription and trigger free radical–induced DNA damage

Abstract: Mitochondrial protein-linked DNA repair promotes gene transcription and protects from free radical–induced DNA damage.

Cited by 49 publications

References 75 publications

Mitochondrial 8-hydroxy-2′-deoxyguanosine and coronary artery disease in patients with type 2 diabetes mellitus

Mitochondrial 8-hydroxy-2′-deoxyguanosine and coronary artery disease in patients with type 2 diabetes mellitus

TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

UVA-induced carbon-centred radicals in lightly pigmented cells detected using ESR spectroscopy

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