scholarly journals Current and emerging roles of Cockayne syndrome group B (CSB) protein

2021 ◽  
Author(s):  
Vinod Tiwari ◽  
Beverly A Baptiste ◽  
Mustafa N Okur ◽  
Vilhelm A Bohr
Keyword(s):  
Genome Stability ◽  
Excision Repair ◽  
Redox Homeostasis ◽  
Cockayne Syndrome ◽  
Cellular Systems ◽  
Premature Aging ◽  
Rdna Transcription ◽  
Molecular Features ◽  
Base Excision ◽  
Group B

Abstract Cockayne syndrome (CS) is a segmental premature aging syndrome caused primarily by defects in the CSA or CSB genes. In addition to premature aging, CS patients typically exhibit microcephaly, progressive mental and sensorial retardation and cutaneous photosensitivity. Defects in the CSB gene were initially thought to primarily impair transcription-coupled nucleotide excision repair (TC-NER), predicting a relatively consistent phenotype among CS patients. In contrast, the phenotypes of CS patients are pleiotropic and variable. The latter is consistent with recent work that implicates CSB in multiple cellular systems and pathways, including DNA base excision repair, interstrand cross-link repair, transcription, chromatin remodeling, RNAPII processing, nucleolin regulation, rDNA transcription, redox homeostasis, and mitochondrial function. The discovery of additional functions for CSB could potentially explain the many clinical phenotypes of CSB patients. This review focuses on the diverse roles played by CSB in cellular pathways that enhance genome stability, providing insight into the molecular features of this complex premature aging disease.

scholarly journals Oxygen-Dependent Accumulation of Purine DNA Lesions in Cockayne Syndrome Cells

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1671 ◽  
Author(s):  
Marios G. Krokidis ◽  
Mariarosaria D’Errico ◽  
Barbara Pascucci ◽  
Eleonora Parlanti ◽  
Annalisa Masi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Enzymatic Digestion ◽  
Cockayne Syndrome ◽  
Dna Lesions ◽  
Premature Aging ◽  
Neurological Features ◽  
Oxygen Tensions ◽  
Base Excision

Cockayne Syndrome (CS) is an autosomal recessive neurodegenerative premature aging disorder associated with defects in nucleotide excision repair (NER). Cells from CS patients, with mutations in CSA or CSB genes, present elevated levels of reactive oxygen species (ROS) and are defective in the repair of a variety of oxidatively generated DNA lesions. In this study, six purine lesions were ascertained in wild type (wt) CSA, defective CSA, wtCSB and defective CSB-transformed fibroblasts under different oxygen tensions (hyperoxic 21%, physioxic 5% and hypoxic 1%). In particular, the four 5′,8-cyclopurine (cPu) and the two 8-oxo-purine (8-oxo-Pu) lesions were accurately quantified by LC-MS/MS analysis using isotopomeric internal standards after an enzymatic digestion procedure. cPu levels were found comparable to 8-oxo-Pu in all cases (3–6 lesions/106 nucleotides), slightly increasing on going from hyperoxia to physioxia to hypoxia. Moreover, higher levels of four cPu were observed under hypoxia in both CSA and CSB-defective cells as compared to normal counterparts, along with a significant enhancement of 8-oxo-Pu. These findings revealed that exposure to different oxygen tensions induced oxidative DNA damage in CS cells, repairable by NER or base excision repair (BER) pathways. In NER-defective CS patients, these results support the hypothesis that the clinical neurological features might be connected to the accumulation of cPu. Moreover, the elimination of dysfunctional mitochondria in CS cells is associated with a reduction in the oxidative DNA damage.

scholarly journals The role of Cockayne Syndrome group B (CSB) protein in base excision repair and aging

2008 ◽  
Vol 129 (7-8) ◽  
pp. 441-448 ◽  
Author(s):  
Tinna Stevnsner ◽  
Meltem Muftuoglu ◽  
Maria Diget Aamann ◽  
Vilhelm A. Bohr
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Cockayne Syndrome ◽  
Base Excision ◽  
Group B

scholarly journals The Cockayne Syndrome Group B Gene Product Is Involved in General Genome Base Excision Repair of 8-Hydroxyguanine in DNA

2001 ◽  
Vol 276 (49) ◽  
pp. 45772-45779 ◽  
Author(s):  
Jingsheng Tuo ◽  
Meltem Müftüoglu ◽  
Catheryne Chen ◽  
Pawel Jaruga ◽  
Rebecca R. Selzer ◽  
...  
Keyword(s):  
Gene Product ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Cockayne Syndrome ◽  
Base Excision ◽  
Group B

scholarly journals Poly(ADP-ribose) polymerase 1 (PARP1) promotes oxidative stress–induced association of Cockayne syndrome group B protein with chromatin

2018 ◽  
Vol 293 (46) ◽  
pp. 17863-17874 ◽  
Author(s):  
Erica L. Boetefuer ◽  
Robert J. Lake ◽  
Kostiantyn Dreval ◽  
Hua-Ying Fan
Keyword(s):  
Oxidative Stress ◽  
Dna Repair ◽  
Rna Polymerase Ii ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Transcription Elongation ◽  
Cockayne Syndrome ◽  
Base Excision ◽  
Group B ◽  
Genomic Regions

Cockayne syndrome protein B (CSB) is an ATP-dependent chromatin remodeler that relieves oxidative stress by regulating DNA repair and transcription. CSB is proposed to participate in base-excision repair (BER), the primary pathway for repairing oxidative DNA damage, but exactly how CSB participates in this process is unknown. It is also unclear whether CSB contributes to other repair pathways during oxidative stress. Here, using a patient-derived CS1AN-sv cell line, we examined how CSB is targeted to chromatin in response to menadione-induced oxidative stress, both globally and locus-specifically. We found that menadione-induced, global CSB–chromatin association does not require CSB's ATPase activity and is, therefore, mechanistically distinct from UV-induced CSB–chromatin association. Importantly, poly(ADP-ribose) polymerase 1 (PARP1) enhanced the kinetics of global menadione-induced CSB–chromatin association. We found that the major BER enzymes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1), do not influence this association. Additionally, the level of γ-H2A histone family member X (γ-H2AX), a marker for dsDNA breaks, was not increased in menadione-treated cells. Therefore, our results support a model whereby PARP1 localizes to ssDNA breaks and recruits CSB to participate in DNA repair. Furthermore, this global CSB–chromatin association occurred independently of RNA polymerase II–mediated transcription elongation. However, unlike global CSB–chromatin association, both PARP1 knockdown and inhibition of transcription elongation interfered with menadione-induced CSB recruitment to specific genomic regions. This observation supports the hypothesis that CSB is also targeted to specific genomic loci to participate in transcriptional regulation in response to oxidative stress.

scholarly journals Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin

2020 ◽  
Author(s):  
Albino Bacolla ◽  
Shiladitya Sengupta ◽  
Zu Ye ◽  
Chunying Yang ◽  
Joy Mitra ◽  
...  
Keyword(s):  
Genome Stability ◽  
High Throughput Sequencing ◽  
Excision Repair ◽  
Essential Gene ◽  
Atmospheric Oxygen ◽  
Super Resolution ◽  
Population Variation ◽  
Mutation Rates ◽  
Open Chromatin ◽  
Base Excision

Abstract Human genome stability requires efficient repair of oxidized bases, which is initiated via damage recognition and excision by NEIL1 and other base excision repair (BER) pathway DNA glycosylases (DGs). However, the biological mechanisms underlying detection of damaged bases among the million-fold excess of undamaged bases remain enigmatic. Indeed, mutation rates vary greatly within individual genomes, and lesion recognition by purified DGs in the chromatin context is inefficient. Employing super-resolution microscopy and co-immunoprecipitation assays, we find that acetylated NEIL1 (AcNEIL1), but not its non-acetylated form, is predominantly localized in the nucleus in association with epigenetic marks of uncondensed chromatin. Furthermore, chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) revealed non-random AcNEIL1 binding near transcription start sites of weakly transcribed genes and along highly transcribed chromatin domains. Bioinformatic analyses revealed a striking correspondence between AcNEIL1 occupancy along the genome and mutation rates, with AcNEIL1-occupied sites exhibiting fewer mutations compared to AcNEIL1-free domains, both in cancer genomes and in population variation. Intriguingly, from the evolutionarily conserved unstructured domain that targets NEIL1 to open chromatin, its damage surveillance of highly oxidation-susceptible sites to preserve essential gene function and to limit instability and cancer likely originated ∼500 million years ago during the buildup of free atmospheric oxygen.

scholarly journals XRCC1 Prevents Replication Fork Instability during Misincorporation of the DNA Demethylation Bases 5-Hydroxymethyl-2′-Deoxycytidine and 5-Hydroxymethyl-2′-Deoxyuridine

2022 ◽  
Vol 23 (2) ◽  
pp. 893
Author(s):  
María José Peña-Gómez ◽  
Marina Suárez-Pizarro ◽  
Iván V. Rosado
Keyword(s):  
Genomic Instability ◽  
Base Excision Repair ◽  
Replication Fork ◽  
Genome Stability ◽  
Excision Repair ◽  
Embryonic Stem ◽  
Dna Demethylation ◽  
Dna Bases ◽  
Stem Cell Pluripotency ◽  
Base Excision

Whilst avoidance of chemical modifications of DNA bases is essential to maintain genome stability, during evolution eukaryotic cells have evolved a chemically reversible modification of the cytosine base. These dynamic methylation and demethylation reactions on carbon-5 of cytosine regulate several cellular and developmental processes such as embryonic stem cell pluripotency, cell identity, differentiation or tumourgenesis. Whereas these physiological processes are well characterized, very little is known about the toxicity of these cytosine analogues when they incorporate during replication. Here, we report a role of the base excision repair factor XRCC1 in protecting replication fork upon incorporation of 5-hydroxymethyl-2′-deoxycytosine (5hmC) and its deamination product 5-hydroxymethyl-2′-deoxyuridine (5hmU) during DNA synthesis. In the absence of XRCC1, 5hmC exposure leads to increased genomic instability, replication fork impairment and cell lethality. Moreover, the 5hmC deamination product 5hmU recapitulated the genomic instability phenotypes observed by 5hmC exposure, suggesting that 5hmU accounts for the observed by 5hmC exposure. Remarkably, 5hmC-dependent genomic instability and replication fork impairment seen in Xrcc1−/− cells were exacerbated by the trapping of Parp1 on chromatin, indicating that XRCC1 maintains replication fork stability during processing of 5hmC and 5hmU by the base excision repair pathway. Our findings uncover natural epigenetic DNA bases 5hmC and 5hmU as genotoxic nucleosides that threaten replication dynamics and genome integrity in the absence of XRCC1.

scholarly journals The ATPase Domain but Not the Acidic Region of Cockayne Syndrome Group B Gene Product Is Essential for DNA Repair

1999 ◽  
Vol 10 (11) ◽  
pp. 3583-3594 ◽  
Author(s):  
Robert M. Brosh ◽  
Adayabalam S. Balajee ◽  
Rebecca R. Selzer ◽  
Morten Sunesen ◽  
Luca Proietti De Santis ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Uv Light ◽  
Genetic Disorder ◽  
Cockayne Syndrome ◽  
Premature Aging ◽  
Atpase Domain ◽  
Acidic Region

Cockayne syndrome (CS) is a human genetic disorder characterized by UV sensitivity, developmental abnormalities, and premature aging. Two of the genes involved, CSA andCSB, are required for transcription-coupled repair (TCR), a subpathway of nucleotide excision repair that removes certain lesions rapidly and efficiently from the transcribed strand of active genes. CS proteins have also been implicated in the recovery of transcription after certain types of DNA damage such as those lesions induced by UV light. In this study, site-directed mutations have been introduced to the human CSB gene to investigate the functional significance of the conserved ATPase domain and of a highly acidic region of the protein. The CSB mutant alleles were tested for genetic complementation of UV-sensitive phenotypes in the human CS-B homologue of hamster UV61. In addition, theCSB mutant alleles were tested for their ability to complement the sensitivity of UV61 cells to the carcinogen 4-nitroquinoline-1-oxide (4-NQO), which introduces bulky DNA adducts repaired by global genome repair. Point mutation of a highly conserved glutamic acid residue in ATPase motif II abolished the ability of CSB protein to complement the UV-sensitive phenotypes of survival, RNA synthesis recovery, and gene-specific repair. These data indicate that the integrity of the ATPase domain is critical for CSB function in vivo. Likewise, the CSB ATPase point mutant failed to confer cellular resistance to 4-NQO, suggesting that ATP hydrolysis is required for CSB function in a TCR-independent pathway. On the contrary, a large deletion of the acidic region of CSB protein did not impair the genetic function in the processing of either UV- or 4-NQO-induced DNA damage. Thus the acidic region of CSB is likely to be dispensable for DNA repair, whereas the ATPase domain is essential for CSB function in both TCR-dependent and -independent pathways.

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

2020 ◽  
Author(s):  
Mustafa N. Okur ◽  
Evandro F. Fang ◽  
Elayne M. Fivenson ◽  
Vinod Tiwari ◽  
Deborah L. Croteau ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Excision Repair ◽  
Mitochondrial Dynamics ◽  
Accelerated Aging ◽  
Cockayne Syndrome ◽  
Premature Aging ◽  
Postmortem Brain ◽  
Average Life Expectancy ◽  
Postmortem Brain Tissue ◽  
Genes Encoding

AbstractBackgroundCockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematodes and CS patients are not fully known.ResultsOur cross-species transcriptomic analysis in CS postmortem brain tissue, CS mouse and nematode models show that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with NAD+ supplementation.ConclusionsOur study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together these three agents contribute to an accelerated aging program that can be averted by NAD+ supplementation.

scholarly journals A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets

2018 ◽  
Vol 215 (3) ◽  
pp. 761-771 ◽  
Author(s):  
Ángel F. Álvarez-Prado ◽  
Pablo Pérez-Durán ◽  
Arantxa Pérez-García ◽  
Alberto Benguria ◽  
Carlos Torroja ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Excision Repair ◽  
Mutagenic Activity ◽  
Predictive Tool ◽  
Chromosome Translocations ◽  
Molecular Features ◽  
Antibody Diversification ◽  
Base Excision ◽  
Activation Induced Deaminase

Activation-induced deaminase (AID) initiates antibody diversification in germinal center (GC) B cells through the deamination of cytosines on immunoglobulin genes. AID can also target other regions in the genome, triggering mutations or chromosome translocations, with major implications for oncogenic transformation. However, understanding the specificity of AID has proved extremely challenging. We have sequenced at very high depth >1,500 genomic regions from GC B cells and identified 275 genes targeted by AID, including 30 of the previously known 35 AID targets. We have also identified the most highly mutated hotspot for AID activity described to date. Furthermore, integrative analysis of the molecular features of mutated genes coupled to machine learning has produced a powerful predictive tool for AID targets. We also have found that base excision repair and mismatch repair back up each other to faithfully repair AID-induced lesions. Finally, our data establish a novel link between AID mutagenic activity and lymphomagenesis.

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