Genome Integrity and Neurological Disease

Scheijen, Elle E. M.; Wilson, David M.

doi:10.3390/ijms23084142

Cited by 11 publications

(11 citation statements)

References 140 publications

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“…SIRTs and nervous system diseases. Nervous system diseases directly affect the lives of hundreds of millions of people worldwide, 733 and one in every nine people dies due to a disorder of the nervous system. 734 Recently, there has been a gradual increase in research on the role of SIRTs in neurological diseases.…”

Section: ) Other Intestinal Diseasesmentioning

confidence: 99%

The sirtuin family in health and disease

Zhang

Chen

et al. 2022

Sig Transduct Target Ther

223

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Sirtuins (SIRTs) are nicotine adenine dinucleotide(+)-dependent histone deacetylases regulating critical signaling pathways in prokaryotes and eukaryotes, and are involved in numerous biological processes. Currently, seven mammalian homologs of yeast Sir2 named SIRT1 to SIRT7 have been identified. Increasing evidence has suggested the vital roles of seven members of the SIRT family in health and disease conditions. Notably, this protein family plays a variety of important roles in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis, etc., thus, it is considered a potential therapeutic target for different kinds of pathologies including cancer, cardiovascular disease, respiratory disease, and other conditions. Moreover, identification of SIRT modulators and exploring the functions of these different modulators have prompted increased efforts to discover new small molecules, which can modify SIRT activity. Furthermore, several randomized controlled trials have indicated that different interventions might affect the expression of SIRT protein in human samples, and supplementation of SIRT modulators might have diverse impact on physiological function in different participants. In this review, we introduce the history and structure of the SIRT protein family, discuss the molecular mechanisms and biological functions of seven members of the SIRT protein family, elaborate on the regulatory roles of SIRTs in human disease, summarize SIRT inhibitors and activators, and review related clinical studies.

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Section: ) Other Intestinal Diseasesmentioning

confidence: 99%

The sirtuin family in health and disease

Zhang

Chen

et al. 2022

Sig Transduct Target Ther

223

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“…More complex lesions that block the progress of RNA or DNA polymerases can result in arrested transcription or replication, respectively, leading to senescence or cell death—fates that culminate in degenerative diseases typically associated with aging [ 11 ]. The CNS is especially prone to degeneration following persistent DNA damage accumulation, primarily as a result of the post-mitotic character of neuronal cells but also due to the limited DNA repair repertoire associated with non-proliferating cells [ 12 ]. The review here will present data that support the role of oxidative DNA damage in the pathogenic process of an SCI, though findings are often contradictory, with broad gaps in our current knowledge.…”

Section: Spinal Cord Injurymentioning

confidence: 99%

“…If these lesions remain unresolved, several detrimental outcomes could occur, such as mutagenesis, DNA replication fork collapse, or RNA transcription blockage, leading to cellular outcomes such as transformation, apoptosis, or senescence. Fortunately, organisms have developed several repair mechanisms to resolve DNA damage and restore DNA to its natural state [ 11 , 12 ]. Depending on the type of DNA lesion, a different mechanism is called upon.…”

Section: The Dna Damage Response Is Understudied In Scimentioning

confidence: 99%

“…The most researched pathway in SCI is BER, likely since BER has a central role in resolving a wide range of oxidative DNA base and sugar lesions. However, it is essential to investigate other DNA repair pathways in greater depth, particularly NER and NHEJ, as these are highly relevant to non-dividing cells such as neurons [ 12 ]. Moreover, only two studies performed a cell type-specific analysis [ 46 , 79 ], whereas the rest analyzed DNA repair in the total spinal cord.…”

Section: The Dna Damage Response Is Understudied In Scimentioning

confidence: 99%

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Oxidative DNA Damage in the Pathophysiology of Spinal Cord Injury: Seems Obvious, but Where Is the Evidence?

2022

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Oxidative stress occurs at various phases of spinal cord injury (SCI), promoting detrimental processes such as free radical injury of proteins, nucleic acids, lipids, cytoskeleton, and organelles. Oxidative DNA damage is likely a major contributor to the pathogenesis of SCI, as a damaged genome cannot be simply turned over to avert detrimental molecular and cellular outcomes, most notably cell death. Surprisingly, the evidence to support this hypothesis is limited. There is some evidence that oxidative DNA damage is increased following SCI, mainly using comet assays and immunohistochemistry. However, there is great variability in the timing and magnitude of its appearance, likely due to differences in experimental models, measurement techniques, and the rigor of the approach. Evidence indicates that 8-oxodG is most abundant at 1 and 7 days post-injury (dpi), while DNA strand breaks peak at 7 and 28 dpi. The DNA damage response seems to be characterized by upregulation of PCNA and PARP1 but downregulation of APEX1. Significant improvements in the analysis of oxidative DNA damage and repair after SCI, including single-cell analysis at time points representative for each phase post-injury using new methodologies and better reporting, will uncover the role of DNA damage and repair in SCI.

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“…Mitochondrial dysfunction is a shared hallmark of aging and neurodegeneration caused by persistent oxidative stress and increased mitochondrial Ca 2+ uptake, leading to the impairment of the electron transport chain and a decrease in ATP production. , Considerable efforts have been made to identify the key molecular determinants for these pathogenic events, and several candidates have been identified. − We have previously shown that mitochondria-targeting electron and radical scavengers, e.g., nitroxides XJB-5-131 and JP4-039, are effective in vivo to mediate injury-induced neuronal death and delay the onset of neurodegenerative diseases such as HD, TBI, and progeria. − These results inspired us to investigate the effect of mitochondria-targeting PARP-1 inhibitors . The poly(ADP-ribose) polymerase (PARP) family of enzymes plays an important role in DNA repair, genome maintenance, chromatin remodeling, transcription regulation, stress response, and regulation of cell death. , PARPs catalyze the PARylation of target proteins by tagging them with polymers of ADP-ribose (PAR), using NAD + as substrate, and releasing nicotinamide as a side-product.…”

mentioning

confidence: 99%

Synthesis of Veliparib Prodrugs and Determination of Drug-Release-Dependent PARP-1 Inhibition

Borgini

Wipf

2023

ACS Med. Chem. Lett.

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Poly(ADP-ribose) polymerase (PARP) plays a key role in repairing DNA damage, and several PARP inhibitors have been approved as treatments in BRCA1/2 mutated breast and ovarian cancers. Mounting evidence also supports their application as neuroprotective agents since PARP overactivation compromises the mitochondrial homeostasis by consumption of NAD+ reserves, leading to an increase in reactive oxygen and nitrogen species and a spike in intracellular Ca2+ levels. Herein, we present the synthesis and preliminary evaluation of new mitochondria-targeting PARP inhibitor prodrugs of (±)-veliparib, with the goal to advance potential neuroprotective properties without impairing the repair of damaged DNA in the nucleus.

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Genome Integrity and Neurological Disease

Cited by 11 publications

References 140 publications

The sirtuin family in health and disease

The sirtuin family in health and disease

Oxidative DNA Damage in the Pathophysiology of Spinal Cord Injury: Seems Obvious, but Where Is the Evidence?

Synthesis of Veliparib Prodrugs and Determination of Drug-Release-Dependent PARP-1 Inhibition

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