SUMOylation of Nuclear γ-Actin by SUMO2 supports DNA Damage Repair against Myocardial Ischemia-Reperfusion Injury

Zhao, Wei; Zhang, Xiuying; Zhao, Jia; Fan, Ni

doi:10.7150/ijbs.74407

Cited by 12 publications

(4 citation statements)

References 64 publications

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“…Ferroptosis is a core remodeling event after myocardial I/R injury and brings the new gospel to the prevention and management of the disease [ 8 ]. Post-translational modifications, such as histone methylation, acetylation, phosphorylation, ubiquitylation, SUMOylation, noncoding RNAs, and m6A modification, participate in the regulation of myocardial I/R injury [ 43 , 44 ]. In the current study, we identified METTL14, miR-146a-5p, and APPL1 as regulators of H/R-induced cardiomyocyte ferroptosis and unified them into a novel molecular route wherein METTL14 upregulates m6A methylation on pri-miR-146a-5p to induce the recognition and processing of pri-miR-146a-5p by DGCR8 leading to increased miR-146a-5p expression and further inhibits APPL1 transcription, consequently promoting H/R-induced cardiomyocyte ferroptosis (Fig.…”

Section: Discussionmentioning

confidence: 99%

METTL14-mediated N6-methyladenosine modification induces the ferroptosis of hypoxia/reoxygenation-induced cardiomyocytes

Zhao,

2024

J Cardiothorac Surg

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Background Hypoxia/reoxygenation (H/R) induces cardiomyocyte ferroptosis, a core remodeling event in myocardial ischemia/reperfusion injury. Methyltransferase-like 14 (METTL14) emerges as a writer of N6-methyladenosine (m6A) modification. This study was conducted to decipher the role of METTL14 in H/R-induced cardiomyocyte ferroptosis. Methods Mouse cardiomyocytes HL-1 were cultured and underwent H/R treatment. The degree of ferroptosis after H/R treatment was appraised by the cell counting kit-8 assay, assay kits (ROS/GSH/Fe2+), and Western blotting (GPX4/ACSL4). The intracellular expressions of METTL14, pri-miR-146a-5p, miR-146a-5p, or adaptor protein phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) were examined by real-time quantitative polymerase chain reaction or Western blotting, with m6A quantification analysis and RNA immunoprecipitation to determine the total m6A level and the expression of pri-miR-146a-5p bound to DiGeorge critical region 8 (DGCR8) and m6A-modified pri-miR-146a-5p. The binding of miR-146a-5p to APPL1 was testified by the dual-luciferase assay. Results H/R treatment induced cardiomyocyte ferroptosis (increased ROS, Fe2+, and ACSL4 and decreased GSH and GPX4) and upregulated METTL14 expression. METTL14 knockdown attenuated H/R-induced cardiomyocyte ferroptosis. METTL14 induced the recognition of pri-miR-146a-5p by DGCR8 by increasing m6A modification on pri-miR-146a-5p, which promoted the conversion of pri-miR-146a-5p into miR-146a-5p and further repressed APPL1 transcription. miR-146a-5p upregulation or APPL1 downregulation limited the inhibitory effect of METTL14 downregulation on H/R-induced cardiomyocyte ferroptosis. Conclusion METTL14 promoted miR-146a-5p expression through the recognition and processing of pri-miR-146a-5p by DGCR8, which repressed APPL1 transcription and triggered H/R-induced cardiomyocyte ferroptosis.

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Section: Discussionmentioning

confidence: 99%

METTL14-mediated N6-methyladenosine modification induces the ferroptosis of hypoxia/reoxygenation-induced cardiomyocytes

Zhao,

2024

J Cardiothorac Surg

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“…In the mature gamete, topoisomerase appears to be activated following its association with small ubiquitin-like modifier 1 (SUMO1). 71 Interestingly, SUMOylation of proteins is known to be promoted by oxidative stress signals [72][73][74] double-strand breaks in stressed germ cells and to associate specifically with topoisomerase. 75 Given this chain of known associations it is possible to elaborate a novel hypothesis about the origins of DNA damage in spermatozoa.…”

Section: How Is It Induced?mentioning

confidence: 99%

“…In the mature gamete, topoisomerase appears to be activated following its association with small ubiquitin‐like modifier 1 (SUMO1) 71 . Interestingly, SUMOylation of proteins is known to be promoted by oxidative stress signals 72–74 and high concentrations of hydrogen peroxide have been shown to stimulate the SUMOylation of proteins in mouse testicular germ cells. Furthermore, in this cell type SUMO has been shown to localize to the sites of DNA double‐strand breaks in stressed germ cells and to associate specifically with topoisomerase 75 …”

Section: Dna Damage In Spermatozoamentioning

confidence: 99%

DNA damage in testicular germ cells and spermatozoa. When and how is it induced? How should we measure it? What does it mean?

Aitken

Lewis

2023

Andrology

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This review surveys the causes and consequences of DNA damage in the male germ line from spermatogonial stem cells to fully differentiated spermatozoa. Within the stem cell population, DNA integrity is well maintained as a result of excellent DNA surveillance and repair; however, a progressive increase in background mutation rates does occur with paternal age possibly as a result of aberrant DNA repair as well as replication error. Once a germ cell has committed to spermatogenesis, it responds to genetic damage via a range of DNA repair pathways or, if this process fails, by the induction of apoptosis. When fully‐differentiated spermatozoa are stressed, they also activate a truncated intrinsic apoptotic pathway which results in the activation of nucleases in the mitochondria and cytoplasm; however, the physical architecture of these cells prevents these enzymes from translocating to the nucleus to induce DNA fragmentation. Conversely, hydrogen peroxide released from the sperm midpiece during apoptosis is able to penetrate the nucleus and induce DNA damage. The base excision repair pathway responds to such damage by cleaving oxidized bases from the DNA, leaving abasic sites that are alkali‐labile and readily detected with the comet assay. As levels of oxidative stress increase and these cells enter the perimortem, topoisomerase integrated into the sperm chromatin becomes activated by SUMOylation. Such activation may initially facilitate DNA repair by reannealing double strand breaks but ultimately prepares the DNA for destruction by nucleases released from the male reproductive tract. The abasic sites and oxidized base lesions found in live spermatozoa are mutagenic and may increase the mutational load carried by the offspring, particularly in the context of assisted conception. A variety of strategies are described for managing patients expressing high levels of DNA damage in their spermatozoa, to reduce the risks such lesions might pose to offspring health.

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“…Acute myocardial infarction (AMI) has become the leading cause of death 1 . Reperfusion therapy is the most effective approach for AMI but frequently causes myocardial ischemia–reperfusion injury (MIRI) leading to myocardial stunning, reperfusion arrhythmias and adverse cardiac remodeling 2 . Numerous studies have demonstrated that the molecular mechanism underlying MIRI involves the accumulation of inf lammatory factors, the generation of reactive oxygen species (ROS), destabilization of lysosomes, potassium efflux and DNA damage 3 – 5 .Reperfusion therapy is the most effective approach for AMI but frequently cause myocardial ischemia–reperfusion injury (MIRI) leading to myocardial stunning and reperfusion arrhythmias, et al Massive researches confirm that the molecular mechanism in myocardial I/R injury could be mediated through increased inflammation, reactive oxygen species (ROS) generation, lysosomal destabilization and potassium efflux 4 , 5 .…”

Section: Introductionmentioning

confidence: 99%

Chlorogenic acid protects against myocardial ischemia–reperfusion injury in mice by inhibiting Lnc Neat1/NLRP3 inflammasome-mediated pyroptosis

Chai,

Liang,

Zhang

et al. 2023

Sci Rep

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Increasing evidences demonstrate that chlorogenic acid (CGA), a polyphenol with multiple effects such as anti-inflammatory and anti-oxidation, protects against myocardial ischemia–reperfusion injury (MIRI) in vitro and in vivo. But its detailed cardiac protection mechanism is still unclear. The MIRI mice model was established by ligating the left anterior descending branch (LAD) of the left coronary artery in C57BL/6 mice. Sixty C57BL/6 mice were randomly divided into four groups. CGA group and CGA + I/R group (each group n = 15) were gavaged with 30 mg/kg/day CGA for 4 weeks. Sham group and I/R group mice (each group n = 15) were administered equal volumes of saline. In vitro MIRI model was constructed by hypoxia and reoxygenation of HL-1 cardiomyocytes. The results showed that CGA pretreatment reduced myocardial infarction size and cTnT contents in serum, simultaneously reduced the levels of Lnc Neat1 expression and attenuated NLRP3 inflammasome-mediated pyroptosis in myocardial tissue. Consistent with in vivo results, the pretreatment of 0.2 μM and 2 μM CGA for 12 h in HL-1 cardiomyocytes depressed hypoxia/reoxygenation-induced Lnc Neat1 expression, NLRP3 inflammasome activation and pyroptosis. Lnc Neat1 shRNA transfection mediated by lentivirus in HL-1 cardiomyocytes significantly reduced activation of NLRP3 inflammasome and pyroptosis. Our findings suggest that CGA protects against MIRI by depressing Lnc Neat1 expression and NLRP3 inflammasome-mediated pyrotosis. Inhibiting the levels of Lnc Neat1 expression may be a therapeutic strategy for MIRI.

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SUMOylation of Nuclear γ-Actin by SUMO2 supports DNA Damage Repair against Myocardial Ischemia-Reperfusion Injury

Cited by 12 publications

References 64 publications

METTL14-mediated N6-methyladenosine modification induces the ferroptosis of hypoxia/reoxygenation-induced cardiomyocytes

METTL14-mediated N6-methyladenosine modification induces the ferroptosis of hypoxia/reoxygenation-induced cardiomyocytes

DNA damage in testicular germ cells and spermatozoa. When and how is it induced? How should we measure it? What does it mean?

Chlorogenic acid protects against myocardial ischemia–reperfusion injury in mice by inhibiting Lnc Neat1/NLRP3 inflammasome-mediated pyroptosis

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