Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

Scheibye‐Knudsen, Morten; Tseng, Anne Hsiao-Hui; Jensen, Martin Borch; Scheibye-Alsing, Karsten; Fang, Evandro Fei; Iyama, Teruaki; Bharti, Sanjay Kumar; Marosi, Krisztina; Froetscher, Lynn; Kassahun, Henok; Eckley, D. Mark; Maul, Robert W.; Bastian, Paul; De, Supriyo; Ghosh, Soumita; Nilsen, Hilde; Goldberg, Ilya G.; Mattson, Mark P.; Wilson, David M.; Brosh, Robert M.; Gorospe, Myriam; Bohr, Vilhelm A.

doi:10.1073/pnas.1610198113

Cited by 79 publications

(96 citation statements)

References 51 publications

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“…PARP1 detects breaks in DNA and recruits DNA repair proteins through a process called PARylation in which PAR chains are generated and NAD + is consumed [53, 94]. PARP1 may also participate in the detection of G4 structures [95]. The accumulation of nuclear DNA damage, which occurs with age [96], can lead to persistent activation of PARP1, which depletes cellular levels of NAD + and reduces sirtuin activity [97].…”

Section: Sirtuins and Mitophagymentioning

confidence: 99%

Mitophagy in neurodegeneration and aging

Fivenson

Lautrup

Sun

et al. 2017

Neurochemistry International

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Mitochondrial dysfunction contributes to normal aging and a wide spectrum of age-related diseases, including neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. It is important to maintain a healthy mitochondrial population which is tightly regulated by proteolysis and mitophagy. Mitophagy is a specialized form of autophagy that regulates the turnover of damaged and dysfunctional mitochondria, organelles that function in producing energy for the cell in the form of ATP and regulating energy homeostasis. Mechanistic studies on mitophagy across species highlight a sophisticated and integrated cellular network that regulates the degradation of mitochondria. Strategies directed at maintaining a healthy mitophagy level in aged individuals might have beneficial effects. In this review, we provide an updated mechanistic overview of mitophagy pathways and discuss the role of reduced mitophagy in neurodegeneration. We also highlight potential translational applications of mitophagy-inducing compounds, such as NAD+ and urolithins.

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Section: Sirtuins and Mitophagymentioning

confidence: 99%

Mitophagy in neurodegeneration and aging

Fivenson

Lautrup

Sun

et al. 2017

Neurochemistry International

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291

183

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“…Similar to other DNA repair-defective premature aging diseases, such as xeroderma pigmentosum (XP)[16], ataxia-telangiectasia (AT) [17], and Werner syndrome (WS) [18], mitochondrial dysfunction is implicated in many CS phenotypes [3, 4, 19]. The mechanisms of mitochondrial dysfunction underlying CS remain unclear but may involve the impairment of the NAD + (nicotinamide adenine dinucleotide, oxidized)-mitophagy axis [19-22].…”

Section: Introductionmentioning

confidence: 99%

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Okur

Fang

Fivenson

et al. 2020

Preprint

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16Background: Cockayne syndrome (CS) is a rare premature aging disease, most 17 commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS 18 patients display cachectic dwarfism and severe neurological manifestations and have 19 an average life expectancy of 12 years. The CS proteins are involved in transcription 20 and DNA repair, with the latter including transcription-coupled nucleotide excision repair 21 (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which 22 likely contributes to the severe premature aging phenotype of this disease. While 23 48 proteins. CSA [5, 6] and CSB [7] are DNA damage response proteins that are involved 49 in transcription-coupled nucleotide excision repair (TC-NER), as well as both nuclear 50 and mitochondrial base excision repair (BER) [8]. NER is a versatile DNA repair 51 pathway as it is responsible for the removal of a wide range of DNA adducts. CSA and 52 CSB are also important for transcription recovery after DNA damage [9][10][11]. Various 53 studies have shown that CSB plays a considerable role in transcription, and likely is a 54 transcription factor [12][13][14][15]. 55 56 Similar to other DNA repair-defective premature aging diseases, such as xeroderma 57 pigmentosum (XP) [16], ataxia-telangiectasia (AT) [17], and Werner syndrome (WS) 58[18], mitochondrial dysfunction is implicated in many CS phenotypes [3, 4, 19]. The 59 mechanisms of mitochondrial dysfunction underlying CS remain unclear but may involve 60 the impairment of the NAD + (nicotinamide adenine dinucleotide, oxidized)-mitophagy 61 axis [19][20][21][22]. NAD + is a fundamental molecule in cellular energy metabolism and 62 signaling pathways and is essential for adaptive responses of cells to bioenergetics and 63 oxidative stress; accordingly, there is an age-dependent depletion of cellular NAD + , 64 suggesting NAD + depletion as a major driver of both pathological and biological aging 65[23]. Many molecular mechanisms are involved in the multi-faceted effects of NAD + on 66 longevity and healthspan, including the induction of mitophagy, a cellular self-67 recognition, engulfment, degradation, and recycling of damaged and superfluous 68 mitochondria [24][25][26]. In CS, the accumulation of unrepaired DNA damage may lead to 69 to those observed in CS patients. After the selection of terms with p-values lower than 130 0.05 and an absolute value pathway Z-Score cut-off of 2.0, the remaining 39 GO terms 131and their respective Z-Scores were sorted by clustering in Fig 1b. Surprisingly, csa-1 132 and csb-1 worms had opposite pathway changes for a majority of the terms. Throughout 133 the dataset, csa-1;csb-1 worms partitioned more with csa-1 than csb-1 worms, 134suggesting that csa-1 drives the double mutant phenotype. However, there was a 135 shortlist of terms, including lysosome, where the csa-1;csb-1 worms segregated with 136 csb-1 worms. Other terms in this group included histidine catabolic process to glutamate 137 and formamide, oxidoreductase activity, an...

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“…Interestingly, primary fibroblasts from CS patients are characterized by increased mitochondrial content, altered membrane potential and increased ROS production (and references therein). Of note, recent data indicate that mitochondrial alteration resulting from the loss of CSA or CSB might be related to stalled ribosomal DNA transcription . Even more, it has been shown that in CS fibroblasts a nuclear transcription deregulation results in increased levels of the HTRA3 serine protease which degrades mitochondrial DNA polymerase gamma, thus, impairing mitochondrial function …”

Section: Molecular Basis Of Overlap Syndromesmentioning

confidence: 99%

Heterogeneity and overlaps in nucleotide excision repair disorders

2019

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Nucleotide excision repair (NER) is an essential DNA repair pathway devoted to the removal of bulky lesions such as photoproducts induced by the ultraviolet (UV) component of solar radiation. Deficiencies in NER typically result in a group of heterogeneous distinct disorders ranging from the mild UV sensitive syndrome to the cancer-prone xeroderma pigmentosum and the neurodevelopmental/progeroid conditions trichothiodystrophy, Cockayne syndrome and cerebro-oculo-facio-skeletalsyndrome. A complicated genetic scenario underlines these disorders with the same gene linked to different clinical entities as well as different genes associated with the same disease. Overlap syndromes with combined hallmark features of different NER disorders can occur and sporadic presentations showing extra features of the hematological disorder Fanconi Anemia or neurological manifestations mimicking Hungtinton disease-like syndromes have been described. Here, we discuss the multiple functions of the five major pleiotropic NER genes (ERCC3/XPB, ERCC2/XPD, ERCC5/ XPG, ERCC1 and ERCC4/XPF) and their relevance in phenotypic complexity. We provide an update of mutational spectra and examine genotype-phenotype relationships.Finally, the molecular defects that could explain the puzzling overlap syndromes are discussed. K E Y W O R D Sgenotype-phenotype relationships, NER disorders, nucleotide excision repair (NER), overlap syndromes

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Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

Cited by 79 publications

References 51 publications

Mitophagy in neurodegeneration and aging

Mitophagy in neurodegeneration and aging

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Heterogeneity and overlaps in nucleotide excision repair disorders

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Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

Cited by 79 publications

References 51 publications

Mitophagy in neurodegeneration and aging

Mitophagy in neurodegeneration and aging

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+signaling

Heterogeneity and overlaps in nucleotide excision repair disorders

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Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling