DNA single-strand break-induced DNA damage response causes heart failure

Higo, Tomoaki; Naito, Atsuhiko T.; Sumida, Tomokazu; Shibamoto, Masato; Okada, Katsuki; Nomura, Seitaro; Nakagawa, Akito; Yamaguchi, Toshihiro; Sakai, Tomohiro; Hashimoto, Akihito; Kuramoto, Yuki; Ito, Masamichi; Hikoso, Shungo; Akazawa, Hiroshi; Lee, Jong-Kook; Shiojima, Ichiro; McKinnon, Peter J.; Sakata, Yasushi; Komuro, Issei

doi:10.1038/ncomms15104

Cited by 102 publications

(82 citation statements)

References 42 publications

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“…However, SSBs can cause serious health disorders as well. It has been proven in a mouse model that the accumulation of SSBs in cardiomyocytes leads to cardiac inflammation in pressure overload-induced heart failure, due to the persistent DNA damage response [17]. To repair SSBs, the base excision repair (BER) mechanism is incorporated during the cell cycle to repair damaged bases.…”

Section: Introductionmentioning

confidence: 99%

Molecular Spectroscopic Markers of DNA Damage

Sofińska¹,

Wilkosz²,

Szymoński³

et al. 2020

Molecules

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Every cell in a living organism is constantly exposed to physical and chemical factors which damage the molecular structure of proteins, lipids, and nucleic acids. Cellular DNA lesions are the most dangerous because the genetic information, critical for the identity and function of each eukaryotic cell, is stored in the DNA. In this review, we describe spectroscopic markers of DNA damage, which can be detected by infrared, Raman, surface-enhanced Raman, and tip-enhanced Raman spectroscopies, using data acquired from DNA solutions and mammalian cells. Various physical and chemical DNA damaging factors are taken into consideration, including ionizing and non-ionizing radiation, chemicals, and chemotherapeutic compounds. All major spectral markers of DNA damage are presented in several tables, to give the reader a possibility of fast identification of the spectral signature related to a particular type of DNA damage.

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Section: Introductionmentioning

confidence: 99%

Molecular Spectroscopic Markers of DNA Damage

Sofińska¹,

Wilkosz²,

Szymoński³

et al. 2020

Molecules

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“…50) DNA double-strand breaks were not increased. Pressure overload induced more severe heart failure in mice lacking XRCC1, an essential SSB repair enzyme, as compared with the control mice, suggesting the causative role of SSB accumulation and DDR activation in the pathogenesis of pressure overload-induced heart failure.…”

Section: Dna Damage Causes Heart Failurementioning

confidence: 83%

Heart Failure as an Aging-Related Phenotype

Morita

Komuro

2018

Int. Heart J.

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SummaryThe molecular pathophysiology of heart failure, which is one of the leading causes of mortality, is not yet fully understood. Heart failure can be regarded as a systemic syndrome of aging-related phenotypes. Wnt/β-catenin signaling and the p53 pathway, both of which are key regulators of aging, have been demonstrated to play a critical role in the pathogenesis of heart failure. Circulating C1q was identified as a novel activator of Wnt/β-catenin signaling, promoting systemic aging-related phenotypes including sarcopenia and heart failure. On the other hand, p53 induces the apoptosis of cardiomyocytes in the failing heart. In these molecular mechanisms, the cross-talk between cardiomyocytes and non-cardiomyocytes (e,g,. endothelial cells, fibroblasts, smooth muscle cells, macrophages) deserves mentioning. In this review, we summarize recent advances in the understanding of the molecular pathophysiology underlying heart failure, focusing on Wnt/β-catenin signaling and the p53 pathway.(Int Heart J 2018; 59: 6-13)

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“…In addition to their significance in genome engineering, nicks occur in normal cellular functions and are relevant to human health and disease. [7][8][9][10][11] Accumulation of nicks can lead to both apoptotic and necrotic cell death 6 as well as dysregulation of cellular processes including transcription and DNA replication. 1 Despite their importance, nicks to date have been less of a focus for study than DSBs.…”

Section: Discussionmentioning

confidence: 99%

“…5 Excessive damage can activate poly(ADP-ribose) polymerase (PARP), a protein capable of identifying nicks, signaling for their repair, and triggering cell death via necrosis or apoptosis. 6 Nicks have also been implicated in heart failure in mouse models through increased expression of inflammatory cytokines 7 and are thought to be a major factor affecting the rate of telomere shortening. 8,9 Ataxia-oculomotor apraxia 1 (AOA1) 10 and spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) 11 are neurodegenerative disorders associated with 2 deficient repair of nicks resulting from abortive DNA ligase and topoisomerase 1 activity, respectively.…”

Section: Introductionmentioning

confidence: 99%

NickSeq for genome-wide strand-specific identification of DNA single-strand break sites with single nucleotide resolution

Elacqua

Ranu

Dilorio

et al. 2019

Preprint

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DNA single-strand breaks (SSBs), or 'nicks', are the most common form of DNA damage. Nicks occur at rates of tens of thousands per cell per day, and result from many sources including oxidative stress and endogenous enzyme activities. Accumulation of nicks, due to high rates of occurrence or defects in repair enzymes, has been implicated in multiple diseases. However, improved methods for nick analysis are needed to learn how their locations and number affect cells, disease progression, and health outcomes. In addition to natural processes including DNA repair, leading genome-editing technologies rely on nuclease activity, including nick generation, at target sites. There is currently a pressing need for methods to study unintended nicking activity genome-wide to evaluate the impact of emerging genome editing tools on cells and organisms. Here we developed a new method, NickSeq, for efficient strand-specific profiling of nicks in complex DNA samples with single nucleotide resolution and low false-positive rates. NickSeq produces deep sequence datasets enriched for reads near nick sites and establishes a readily detectable mutational signal that allows for determination of the nick site and strand. In this work, we apply NickSeq to profile off-target activity of the Nb.BsmI nicking endonuclease and an engineered spCas9 nickase. NickSeq will be useful in exploring the relevance of spontaneously occurring or repair-induced DNA breaks in human disease, DNA breaks caused by DNA damaging agents including therapeutics, and the activity of engineered nucleases in genome editing and other biotechnological applications.

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DNA single-strand break-induced DNA damage response causes heart failure

Cited by 102 publications

References 42 publications

Molecular Spectroscopic Markers of DNA Damage

Molecular Spectroscopic Markers of DNA Damage

Heart Failure as an Aging-Related Phenotype

NickSeq for genome-wide strand-specific identification of DNA single-strand break sites with single nucleotide resolution

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