Artykuły w czasopismach: „Progeroid cockayne syndrome”

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Domino, Joseph S., Rose Gelineau-Morel i Christian Kaufman. "Deep Brain Stimulation for Cockayne Syndrome-Associated Movement Disorder". Journal of Movement Disorders 15, nr 1 (31.01.2022): 62–65. http://dx.doi.org/10.14802/jmd.21005.

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Cockayne syndrome (CS) is a rare progeroid disorder characterized by multisystem degeneration, including neurological dysfunction, for which deep brain stimulation (DBS) is a proposed treatment. This study represents only the third case of DBS for CS-associated movement disorder and the first in which both proposed targets had devices implanted, allowing for direct comparison. A case of DBS for CS-associated movement disorder is presented. Previous literature documents two cases with one targeting the ventral intermediate nucleus of the thalamus (VIM) and the other targeting the globus pallidus interna (GPi). Our patient underwent stimulation of GPi nuclei followed by repositioning to VIM nuclei with improved symptom control using VIM stimulation. In all cases, there was a significant clinical benefit without off-target effects. CS-associated movement disorder exhibits phenotypic variability for which DBS is a viable treatment. Target selection should be driven by clinical phenotype.

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Zayoud, Khouloud, Asma Chikhaoui, Ichraf Kraoua, Anis Tebourbi, Dorra Najjar, Saker Ayari, Ines Safra i in. "Immunity in the Progeroid Model of Cockayne Syndrome: Biomarkers of Pathological Aging". Cells 13, nr 5 (26.02.2024): 402. http://dx.doi.org/10.3390/cells13050402.

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Cockayne syndrome (CS) is a rare autosomal recessive disorder that affects the DNA repair process. It is a progeroid syndrome predisposing patients to accelerated aging and to increased susceptibility to respiratory infections. Here, we studied the immune status of CS patients to determine potential biomarkers associated with pathological aging. CS patients, as well as elderly and young, healthy donors, were enrolled in this study. Complete blood counts for patients and donors were assessed, immune cell subsets were analyzed using flow cytometry, and candidate cytokines were analyzed via multi-analyte ELISArray kits. In CS patients, we noticed a high percentage of lymphocytes, an increased rate of intermediate and non-classical monocytes, and a high level of pro-inflammatory cytokine IL-8. In addition, we identified an increased rate of particular subtypes of T Lymphocyte CD8+ CD28− CD27−, which are senescent T cells. Thus, an inflammatory state was found in CS patients that is similar to that observed in the elderly donors and is associated with an immunosenescence status in both groups. This could explain the CS patients’ increased susceptibility to infections, which is partly due to an aging-associated inflammation process.

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Chatre, Laurent, Denis S. F. Biard, Alain Sarasin i Miria Ricchetti. "Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome". Proceedings of the National Academy of Sciences 112, nr 22 (18.05.2015): E2910—E2919. http://dx.doi.org/10.1073/pnas.1422264112.

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UV-sensitive syndrome (UVSS) and Cockayne syndrome (CS) are human disorders caused by CSA or CSB gene mutations; both conditions cause defective transcription-coupled repair and photosensitivity. Patients with CS also display neurological and developmental abnormalities and dramatic premature aging, and their cells are hypersensitive to oxidative stress. We report CSA/CSB-dependent depletion of the mitochondrial DNA polymerase-γ catalytic subunit (POLG1), due to HTRA3 serine protease accumulation in CS, but not in UVsS or control fibroblasts. Inhibition of serine proteases restored physiological POLG1 levels in either CS fibroblasts and in CSB-silenced cells. Moreover, patient-derived CS cells displayed greater nitroso-redox imbalance than UVSS cells. Scavengers of reactive oxygen species and peroxynitrite normalized HTRA3 and POLG1 levels in CS cells, and notably, increased mitochondrial oxidative phosphorylation, which was altered in CS cells. These data reveal critical deregulation of proteases potentially linked to progeroid phenotypes in CS, and our results suggest rescue strategies as a therapeutic option.

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Kamenisch, York, Maria Fousteri, Jennifer Knoch, Anna-Katharina von Thaler, Birgit Fehrenbacher, Hiroki Kato, Thomas Becker i in. "Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging". Journal of Experimental Medicine 207, nr 2 (25.01.2010): 379–90. http://dx.doi.org/10.1084/jem.20091834.

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Defects in the DNA repair mechanism nucleotide excision repair (NER) may lead to tumors in xeroderma pigmentosum (XP) or to premature aging with loss of subcutaneous fat in Cockayne syndrome (CS). Mutations of mitochondrial (mt)DNA play a role in aging, but a link between the NER-associated CS proteins and base excision repair (BER)-associated proteins in mitochondrial aging remains enigmatic. We show functional increase of CSA and CSB inside mt and complex formation with mtDNA, mt human 8-oxoguanine glycosylase (mtOGG)-1, and mt single-stranded DNA binding protein (mtSSBP)-1 upon oxidative stress. MtDNA mutations are highly increased in cells from CS patients and in subcutaneous fat of aged Csbm/m and Csa−/− mice. Thus, the NER-proteins CSA and CSB localize to mt and directly interact with BER-associated human mitochondrial 8-oxoguanine glycosylase-1 to protect from aging- and stress-induced mtDNA mutations and apoptosis-mediated loss of subcutaneous fat, a hallmark of aging found in animal models, human progeroid syndromes like CS and in normal human aging.

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Pascucci, Barbara, Francesca Spadaro, Donatella Pietraforte, Chiara De Nuccio, Sergio Visentin, Paola Giglio, Eugenia Dogliotti i Mariarosaria D’Errico. "DRP1 Inhibition Rescues Mitochondrial Integrity and Excessive Apoptosis in CS-A Disease Cell Models". International Journal of Molecular Sciences 22, nr 13 (1.07.2021): 7123. http://dx.doi.org/10.3390/ijms22137123.

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Cockayne syndrome group A (CS-A) is a rare recessive progeroid disorder characterized by sun sensitivity and neurodevelopmental abnormalities. Cells derived from CS-A patients present as pathological hallmarks excessive oxidative stress, mitochondrial fragmentation and apoptosis associated with hyperactivation of the mitochondrial fission dynamin related protein 1 (DRP1). In this study, by using human cell models we further investigated the interplay between DRP1 and CSA and we determined whether pharmacological or genetic inhibition of DRP1 affects disease progression. Both reactive oxygen and nitrogen species are in excess in CS-A cells and when the mitochondrial translocation of DRP1 is inhibited a reduction of these species is observed together with a recovery of mitochondrial integrity and a significant decrease of apoptosis. This study indicates that the CSA-driven modulation of DRP1 pathway is key to control mitochondrial homeostasis and apoptosis and suggests DRP1 as a potential target in the treatment of CS patients.

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Andressoo, Jaan-Olle, Geert Weeda, Jan de Wit, James R. Mitchell, Rudolf B. Beems, Harry van Steeg, Gijsbertus T. J. van der Horst i Jan H. Hoeijmakers. "An Xpb Mouse Model for Combined Xeroderma Pigmentosum and Cockayne Syndrome Reveals Progeroid Features upon Further Attenuation of DNA Repair". Molecular and Cellular Biology 29, nr 5 (29.12.2008): 1276–90. http://dx.doi.org/10.1128/mcb.01229-08.

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ABSTRACT Patients carrying mutations in the XPB helicase subunit of the basal transcription and nucleotide excision repair (NER) factor TFIIH display the combined cancer and developmental-progeroid disorder xeroderma pigmentosum/Cockayne syndrome (XPCS). Due to the dual transcription repair role of XPB and the absence of animal models, the underlying molecular mechanisms of XPBXPCS are largely uncharacterized. Here we show that severe alterations in Xpb cause embryonic lethality and that knock-in mice closely mimicking an XPCS patient-derived XPB mutation recapitulate the UV sensitivity typical for XP but fail to show overt CS features unless the DNA repair capacity is further challenged by crossings to the NER-deficient Xpa background. Interestingly, the Xpb XPCS Xpa double mutants display a remarkable interanimal variance, which points to stochastic DNA damage accumulation as an important determinant of clinical diversity in NER syndromes. Furthermore, mice carrying the Xpb XPCS mutation together with a point mutation in the second TFIIH helicase Xpd are healthy at birth but display neonatal lethality, indicating that transcription efficiency is sufficient to permit embryonal development even when both TFIIH helicases are crippled. The double-mutant cells exhibit sensitivity to oxidative stress, suggesting a role for endogenous DNA damage in the onset of XPB-associated CS.

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Wilson, David M., i Vilhelm A. Bohr. "Special Issue on the segmental progeria Cockayne syndrome". Mechanisms of Ageing and Development 134, nr 5-6 (maj 2013): 159–60. http://dx.doi.org/10.1016/j.mad.2013.04.002.

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Shamanuru, Latha Gowdru, Veeresh Babu Doddamane i Veeranna Preeti. "Cockayne syndrome, xeroderma pigmentosa: a rare case report". International Journal of Contemporary Pediatrics 8, nr 3 (23.02.2021): 569. http://dx.doi.org/10.18203/2349-3291.ijcp20210666.

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Cockayne syndrome is a rare autosomal recessive disorder characterized by premature ageing (progeria), facial anomalies, cachectic dwarfism, mental retardation, cutaneous photosensitivity, and retinopathy, loss of adipose tissue and muscle, and neurological abnormality which are associated with the changes in the brain parenchyma. The findings of computed tomography scan and especially magnetic resonance imaging of the brain support the clinical diagnosis of CS. There is no permanent cure of this condition and death usually occurs in the second or third decade due to functional disability and multiple infections.

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de Waard, Harm, Jan de Wit, Jaan-Olle Andressoo, Conny T. M. van Oostrom, Bente Riis, Allan Weimann, Henrik E. Poulsen, Harry van Steeg, Jan H. J. Hoeijmakers i Gijsbertus T. J. van der Horst. "Different Effects of CSA and CSB Deficiency on Sensitivity to Oxidative DNA Damage". Molecular and Cellular Biology 24, nr 18 (15.09.2004): 7941–48. http://dx.doi.org/10.1128/mcb.24.18.7941-7948.2004.

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ABSTRACT Mutations in the CSA and CSB genes cause Cockayne syndrome, a rare inherited disorder characterized by UV sensitivity, severe neurological abnormalities, and progeriod symptoms. Both gene products function in the transcription-coupled repair (TCR) subpathway of nucleotide excision repair (NER), providing the cell with a mechanism to remove transcription-blocking lesions from the transcribed strands of actively transcribed genes. Besides a function in TCR of NER lesions, a role of CSB in (transcription-coupled) repair of oxidative DNA damage has been suggested. In this study we used mouse models to compare the effect of a CSA or a CSB defect on oxidative DNA damage sensitivity at the levels of the cell and the intact organism. In contrast to CSB −/− mouse embryonic fibroblasts (MEFs), CSA −/− MEFs are not hypersensitive to gamma-ray or paraquat treatment. Similar results were obtained for keratinocytes. In contrast, both CSB −/− and CSA −/− embryonic stem cells show slight gamma-ray sensitivity. Finally, CSB −/− but not CSA −/− mice fed with food containing di(2-ethylhexyl)phthalate (causing elevated levels of oxidative DNA damage in the liver) show weight reduction. These findings not only uncover a clear difference in oxidative DNA damage sensitivity between CSA- and CSB-deficient cell lines and mice but also show that sensitivity to oxidative DNA damage is not a uniform characteristic of Cockayne syndrome. This difference in the DNA damage response between CSA- and CSB-deficient cells is unexpected, since until now no consistent differences between CSA and CSB patients have been reported. We suggest that the CSA and CSB proteins in part perform separate roles in different DNA damage response pathways.

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Phan, Tamara, Fatima Khalid i Sebastian Iben. "Nucleolar and Ribosomal Dysfunction—A Common Pathomechanism in Childhood Progerias?" Cells 8, nr 6 (4.06.2019): 534. http://dx.doi.org/10.3390/cells8060534.

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The nucleolus organizes around the sites of transcription by RNA polymerase I (RNA Pol I). rDNA transcription by this enzyme is the key step of ribosome biogenesis and most of the assembly and maturation processes of the ribosome occur co-transcriptionally. Therefore, disturbances in rRNA transcription and processing translate to ribosomal malfunction. Nucleolar malfunction has recently been described in the classical progeria of childhood, Hutchinson–Gilford syndrome (HGPS), which is characterized by severe signs of premature aging, including atherosclerosis, alopecia, and osteoporosis. A deregulated ribosomal biogenesis with enlarged nucleoli is not only characteristic for HGPS patients, but it is also found in the fibroblasts of “normal” aging individuals. Cockayne syndrome (CS) is also characterized by signs of premature aging, including the loss of subcutaneous fat, alopecia, and cataracts. It has been shown that all genes in which a mutation causes CS, are involved in rDNA transcription by RNA Pol I. A disturbed ribosomal biogenesis affects mitochondria and translates into ribosomes with a reduced translational fidelity that causes endoplasmic reticulum (ER) stress and apoptosis. Therefore, it is speculated that disease-causing disturbances in the process of ribosomal biogenesis may be more common than hitherto anticipated.

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Andressoo, Jaan-Olle, James R. Mitchell, Jan de Wit, Deborah Hoogstraten, Marcel Volker, Wendy Toussaint, Ewoud Speksnijder i in. "An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria". Cancer Cell 10, nr 2 (sierpień 2006): 121–32. http://dx.doi.org/10.1016/j.ccr.2006.05.027.

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Brace, Lear E., Sarah C. Vose, Dorathy F. Vargas, Shuangyun Zhao, Xiu-Ping Wang i James R. Mitchell. "Lifespan extension by dietary intervention in a mouse model of Cockayne Syndrome uncouples early postnatal development from segmental progeria". Aging Cell 12, nr 6 (11.09.2013): 1144–47. http://dx.doi.org/10.1111/acel.12142.

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Marín, Maria, María José Ramírez, Miriam Aza Carmona, Nan Jia, Tomoo Ogi, Massimo Bogliolo i Jordi Surrallés. "Functional Comparison of XPF Missense Mutations Associated to Multiple DNA Repair Disorders". Genes 10, nr 1 (17.01.2019): 60. http://dx.doi.org/10.3390/genes10010060.

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XPF endonuclease is one of the most important DNA repair proteins. Encoded by XPF/ERCC4, XPF provides the enzymatic activity of XPF-ERCC1 heterodimer, an endonuclease that incises at the 5’ side of various DNA lesions. XPF is essential for nucleotide excision repair (NER) and interstrand crosslink repair (ICLR). XPF/ERCC4 mutations are associated with several human diseases: Xeroderma Pigmentosum (XP), Segmental Progeria (XFE), Fanconi Anemia (FA), Cockayne Syndrome (CS), and XP/CS combined disease (XPCSCD). Most affected individuals are compound heterozygotes for XPF/ERCC4 mutations complicating the identification of genotype/phenotype correlations. We report a detailed overview of NER and ICLR functional studies in human XPF-KO (knock-out) isogenic cells expressing six disease-specific pathogenic XPF amino acid substitution mutations. Ultraviolet (UV) sensitivity and unscheduled DNA synthesis (UDS) assays provide the most reliable information to discern mutations associated with ICLR impairment from mutations related to NER deficiency, whereas recovery of RNA synthesis (RRS) assays results hint to a possible role of XPF in resolving R-loops. Our functional studies demonstrate that a defined cellular phenotype cannot be easily correlated to each XPF mutation. Substituted positions along XPF sequences are not predictive of cellular phenotype nor reflect a particular disease. Therefore, in addition to mutation type, allelic interactions, protein stability and intracellular distribution of mutant proteins may also contribute to alter DNA repair pathways balance leading to clinically distinct disorders.

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Bramwell, Laura R., i Lorna W. Harries. "Senescence, regulators of alternative splicing and effects of trametinib treatment in progeroid syndromes". GeroScience, 26.09.2023. http://dx.doi.org/10.1007/s11357-023-00933-z.

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AbstractProgeroid syndromes such as Hutchinson Gilford Progeroid syndrome (HGPS), Werner syndrome (WS) and Cockayne syndrome (CS), result in severely reduced lifespans and premature ageing. Normal senescent cells show splicing factor dysregulation, which has not yet been investigated in syndromic senescent cells. We sought to investigate the senescence characteristics and splicing factor expression profiles of progeroid dermal fibroblasts. Natural cellular senescence can be reversed by application of the senomorphic drug, trametinib, so we also investigated its ability to reverse senescence characteristics in syndromic cells. We found that progeroid cultures had a higher senescence burden, but did not always have differences in levels of proliferation, DNA damage repair and apoptosis. Splicing factor gene expression appeared dysregulated across the three syndromes. 10 µM trametinib reduced senescent cell load and affected other aspects of the senescence phenotype (including splicing factor expression) in HGPS and Cockayne syndromes. Werner syndrome cells did not demonstrate changes in in senescence following treatment. Splicing factor dysregulation in progeroid cells provides further evidence to support this mechanism as a hallmark of cellular ageing and highlights the use of progeroid syndrome cells in the research of ageing and age-related disease. This study suggests that senomorphic drugs such as trametinib could be a useful adjunct to therapy for progeroid diseases.

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Bahap, Yusuf, i Gulsum Kayhan. "A Cockayne-Syndrome-Like Phenotype with a Homozygous Truncating UVSSA Variant: Might This Be a New Cause?" Molecular Syndromology, 23.02.2024, 1–4. http://dx.doi.org/10.1159/000536420.

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Introduction: UV-sensitive syndrome and Cockayne syndrome (CS) are rare autosomal recessive and transcription-coupled nucleotide excision repair disorders with different clinical manifestations, although some types are allelic. Case Presentation: We report on a patient who passed away at 15 years old with a progeroid-like appearance, cachexia, hearing loss, and dental anomalies, which led us to the diagnosis of Cockayne-like progeroid syndromes. Our clinical exome sequencing including all the known genes of progeroid syndromes revealed a homozygous stop-gain variant in the UVSSA gene. Conclusion: Although truncating variants in the UVSSA are known to cause UVsS3, their association with CS has not yet been defined. This case might be the first report of a CS-like phenotype caused by a defective UVSSA.

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Crochemore, Clément, Claudia Chica, Paolo Garagnani, Giovanna Lattanzi, Steve Horvath, Alain Sarasin, Claudio Franceschi, Maria Giulia Bacalini i Miria Ricchetti. "Epigenomic signature of accelerated ageing in progeroid Cockayne syndrome". Aging Cell, 8.09.2023. http://dx.doi.org/10.1111/acel.13959.

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AbstractCockayne syndrome (CS) and UV‐sensitive syndrome (UVSS) are rare genetic disorders caused by mutation of the DNA repair and multifunctional CSA or CSB protein, but only CS patients display a progeroid and neurodegenerative phenotype, providing a unique conceptual and experimental paradigm. As DNA methylation (DNAm) remodelling is a major ageing marker, we performed genome‐wide analysis of DNAm of fibroblasts from healthy, UVSS and CS individuals. Differential analysis highlighted a CS‐specific epigenomic signature (progeroid‐related; not present in UVSS) enriched in three categories: developmental transcription factors, ion/neurotransmitter membrane transporters and synaptic neuro‐developmental genes. A large fraction of CS‐specific DNAm changes were associated with expression changes in CS samples, including in previously reported post‐mortem cerebella. The progeroid phenotype of CS was further supported by epigenomic hallmarks of ageing: the prediction of DNAm of repetitive elements suggested an hypomethylation of Alu sequences in CS, and the epigenetic clock returned a marked increase in CS biological age respect to healthy and UVSS cells. The epigenomic remodelling of accelerated ageing in CS displayed both commonalities and differences with other progeroid diseases and regular ageing. CS shared DNAm changes with normal ageing more than other progeroid diseases do, and included genes functionally validated for regular ageing. Collectively, our results support the existence of an epigenomic basis of accelerated ageing in CS and unveil new genes and pathways that are potentially associated with the progeroid/degenerative phenotype.

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Suga, Naoko, Yuka Ikeda, Sayuri Yoshikawa i Satoru Matsuda. "Roles of poly(ADP-ribose) polymerase 1 and mitophagy in progeroid syndromes as well as physiological ageing". Exploration of Medicine, 31.10.2023, 822–38. http://dx.doi.org/10.37349/emed.2023.00180.

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Progeroid syndromes are characterized by clinical signs of premature ageing, which may contain several diseases such as Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford progeria syndrome, and Cockayne syndrome. These disorders may also exhibit some pathological involvements reminiscent of primary mitochondrial diseases. Emerging evidence has linked mitochondria even to physiological ageing. In addition, alterations in the maintenance pathway of mitochondria have been also deliberated as relevant in age-related diseases. In particular, mitophagy and its regulatory pathway might be key process for the homeostasis of mitochondria. Therefore, chronic DNA damage and/or the activation of poly[adenosine diphosphate (ADP)-ribose] polymerase 1 (PARP1) could be a threat to the mitochondrial alterations. The PARP1 is an enzyme responding to the DNA damage, which might be also involved in the mitophagy. Interestingly, the PARP1 has been reported to play an important role in the longevity of lifespan, which has attracted growing attention with the social development. This review may provide a rationalized overview of the involvement of mitochondrial oxidative stresses in genetically defined accelerated ageing, progeroid syndromes, physiological ageing, and/or age-related diseases for the innovative therapeutic approaches.

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Crochemore, Clément, Cristina Fernández-Molina, Benjamin Montagne, Audrey Salles i Miria Ricchetti. "CSB promoter downregulation via histone H3 hypoacetylation is an early determinant of replicative senescence". Nature Communications 10, nr 1 (grudzień 2019). http://dx.doi.org/10.1038/s41467-019-13314-y.

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AbstractCellular senescence has causative links with ageing and age-related diseases, however, it remains unclear if progeroid factors cause senescence in normal cells. Here, we show that depletion of CSB, a protein mutated in progeroid Cockayne syndrome (CS), is the earliest known trigger of p21-dependent replicative senescence. CSB depletion promotes overexpression of the HTRA3 protease resulting in mitochondrial impairments, which are causally linked to CS pathological phenotypes. The CSB promoter is downregulated by histone H3 hypoacetylation during DNA damage-response. Mechanistically, CSB binds to the p21 promoter thereby downregulating its transcription and blocking replicative senescence in a p53-independent manner. This activity of CSB is independent of its role in the repair of UV-induced DNA damage. HTRA3 accumulation and senescence are partially rescued upon reduction of oxidative/nitrosative stress. These findings establish a CSB/p21 axis that acts as a barrier to replicative senescence, and link a progeroid factor with the process of regular ageing in human.

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Paccosi, Elena, Adayabalam S. Balajee i Luca Proietti-De-Santis. "A matter of delicate balance: Loss and gain of Cockayne syndrome proteins in premature aging and cancer". Frontiers in Aging 3 (21.07.2022). http://dx.doi.org/10.3389/fragi.2022.960662.

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DNA repair genes are critical for preserving genomic stability and it is well established that mutations in DNA repair genes give rise to progeroid diseases due to perturbations in different DNA metabolic activities. Cockayne Syndrome (CS) is an autosomal recessive inheritance caused by inactivating mutations in CSA and CSB genes. This review will primarily focus on the two Cockayne Syndrome proteins, CSA and CSB, primarily known to be involved in Transcription Coupled Repair (TCR). Curiously, dysregulated expression of CS proteins has been shown to exhibit differential health outcomes: lack of CS proteins due to gene mutations invariably leads to complex premature aging phenotypes, while excess of CS proteins is associated with carcinogenesis. Thus it appears that CS genes act as a double-edged sword whose loss or gain of expression leads to premature aging and cancer. Future mechanistic studies on cell and animal models of CS can lead to potential biological targets for interventions in both aging and cancer development processes. Some of these exciting possibilities will be discussed in this review in light of the current literature.

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Kulikowska, Joanna, Anna Jakubiuk-Tomaszuk, Małgorzata Rydzanicz, Rafał Płoski, Jan Kochanowicz, Alina Kulakowska i Katarzyna Kapica-Topczewska. "Case report: Variants in the ERCC4 gene as a rare cause of cerebellar ataxia with chorea". Frontiers in Genetics 14 (2.02.2023). http://dx.doi.org/10.3389/fgene.2023.1107460.

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Variants in the ERCC4 gene have been described to be associated with the following autosomal recessive diseases: xeroderma pigmentosum group F (XPF), xeroderma pigmentosum type F/Cockayne syndrome (XPF/CS), Fanconi anemia complementation group Q (FANCQ), and XFE progeroid syndrome (XFEPS). In this paper, we present a case of a 53-year-old Caucasian female patient with rare variants in the ERCC4 gene. When she was 42 years old, falls and loss of balance occurred. At the age of 48, involuntary, uncoordinated movements of the upper limbs and head, tongue stereotypes (licking and extending movements), speech problems (dysarthria), memory deterioration, and hearing loss occurred. Since childhood, she has shown hypersensitivity to UV radiation. The neurological examination revealed chorea syndrome, cerebellar ataxia, dysarthria, and bilateral hearing loss. She has numerous pigmented lesions on the skin. Brain MRI demonstrated massive cortico-subcortical atrophy. The neuropsychological examination revealed dysfunctions in the executive domain in terms of attention, working memory, organizing, and planning activities. The genetic diagnostics was performed which excluded spinocerebellar ataxia types 1, 2, 3, 6, and 17, Huntington’s disease, and FMR1 premutation. In the genetic analysis of next-generation sequencing (NGS), two variants: c.2395C > T and c.1349G > A in the ERCC4 gene were identified in a heterozygote configuration. So far, a few cases of ERCC4 gene variants, which are associated with nucleotide excision repair pathways, have been described in connection with symptoms of cerebellar ataxia. In patients with ERCC4 biallelic variants, the adult neurological phenotype can sometimes be the first symptom and reason for access to genetic testing. The aforementioned case highlights the occurrence of rare genetic causes of progressive neurodegenerative diseases in adults, especially with the spectrum of autosomal recessive nucleotide excision repair pathway disorders (NERDs).

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Milosic, Filip, Markus Hengstschläger i Selma Osmanagic-Myers. "Premature aging in genetic diseases: what conclusions can be drawn for physiological aging". Frontiers in Aging 4 (28.02.2024). http://dx.doi.org/10.3389/fragi.2023.1327833.

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According to current views the major hallmarks of physiological aging may be subdivided into three categories, primary causes of cellular damage (genomic instability, telomere attrition, loss of proteostasis, epigenetic alterations and compromised macroautophagy), antagonistic hallmarks that represent response to damage (deregulated nutrient sensing, cellular senescence, mitochondrial dysfunction) and integrative hallmarks that represent culprits of the phenotype (stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis). In contrast to physiological aging, premature aging diseases are driven by one or two distinct primary causes of aging, such as genomic instability in the case of Werner syndrome (WS), each displaying other hallmarks of aging to a variable extent. In this review we will focus on primary causes of well-investigated premature aging diseases Hutchinson-Gilford progeria syndrome (HGPS), WS, and Cockayne syndrome (CS) and for each provide an overview of reported aging hallmarks to elucidate resemblance to physiological aging on the mechanistic level and in the context of characteristic age-related diseases. Ubiquitous and tissue specific animal models of premature aging diseases will be discussed as useful tools to decipher fundamental aging-related mechanisms and develop intervention strategies to combat premature aging and age-related diseases.

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Oka, Yasuyoshi, Yuka Nakazawa, Mayuko Shimada i Tomoo Ogi. "Endogenous aldehyde-induced DNA–protein crosslinks are resolved by transcription-coupled repair". Nature Cell Biology, 10.04.2024. http://dx.doi.org/10.1038/s41556-024-01401-2.

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AbstractDNA–protein crosslinks (DPCs) induced by aldehydes interfere with replication and transcription. Hereditary deficiencies in DPC repair and aldehyde clearance processes cause progeria, including Ruijs–Aalfs syndrome (RJALS) and AMeD syndrome (AMeDS) in humans. Although the elimination of DPC during replication has been well established, how cells overcome DPC lesions in transcription remains elusive. Here we show that endogenous aldehyde-induced DPC roadblocks are efficiently resolved by transcription-coupled repair (TCR). We develop a high-throughput sequencing technique to measure the genome-wide distribution of DPCs (DPC-seq). Using proteomics and DPC-seq, we demonstrate that the conventional TCR complex as well as VCP/p97 and the proteasome are required for the removal of formaldehyde-induced DPCs. TFIIS-dependent cleavage of RNAPII transcripts protects against transcription obstacles. Finally, a mouse model lacking both aldehyde clearance and TCR confirms endogenous DPC accumulation in actively transcribed regions. Collectively, our data provide evidence that transcription-coupled DPC repair (TC-DPCR) as well as aldehyde clearance are crucial for protecting against metabolic genotoxin, thus explaining the molecular pathogenesis of AMeDS and other disorders associated with defects in TCR, such as Cockayne syndrome.

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