scholarly journals Cockayne Syndrome Group B (CSB): The Regulatory Framework Governing the Multifunctional Protein and Its Plausible Role in Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 866
Author(s):  
Zoi Spyropoulou ◽  
Angelos Papaspyropoulos ◽  
Nefeli Lagopati ◽  
Vassilios Myrianthopoulos ◽  
Alexandros G. Georgakilas ◽  
...  
Keyword(s):  
Dna Repair ◽  
Clinical Manifestations ◽  
Cockayne Syndrome ◽  
Premature Aging ◽  
Telomere Maintenance ◽  
Post Translational Modifications ◽  
Multifunctional Protein ◽  
Developmental Impairment ◽  
Group B ◽  
Syndrome Protein

Cockayne syndrome (CS) is a DNA repair syndrome characterized by a broad spectrum of clinical manifestations such as neurodegeneration, premature aging, developmental impairment, photosensitivity and other symptoms. Mutations in Cockayne syndrome protein B (CSB) are present in the vast majority of CS patients and in other DNA repair-related pathologies. In the literature, the role of CSB in different DNA repair pathways has been highlighted, however, new CSB functions have been identified in DNA transcription, mitochondrial biology, telomere maintenance and p53 regulation. Herein, we present an overview of identified structural elements and processes that impact on CSB activity and its post-translational modifications, known to balance the different roles of the protein not only during normal conditions but most importantly in stress situations. Moreover, since CSB has been found to be overexpressed in a number of different tumors, its role in cancer is presented and possible therapeutic targeting is discussed.

scholarly journals Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane

2010 ◽  
Vol 24 (7) ◽  
pp. 2334-2346 ◽  
Author(s):  
Maria D. Aamann ◽  
Martin M. Sorensen ◽  
Christina Hvitby ◽  
Brian R. Berquist ◽  
Meltem Muftuoglu ◽  
...  
Keyword(s):  
Dna Repair ◽  
Mitochondrial Dna ◽  
Mitochondrial Membrane ◽  
Cockayne Syndrome ◽  
Dna Stability ◽  
Group B ◽  
Mitochondrial Dna Stability

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.

The Cockayne syndrome group B DNA repair protein as an anti-cancer target

2001 ◽  
Author(s):  
Y. Lu ◽  
Sridhar Mani ◽  
Ekambar Kandimalla ◽  
Dong Yu ◽  
Sudhir Agrawal ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cockayne Syndrome ◽  
Repair Protein ◽  
Anti Cancer ◽  
Dna Repair Protein ◽  
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 CSB-Dependent Cyclin-Dependent Kinase 9 Degradation and RNA Polymerase II Phosphorylation during Transcription-Coupled Repair

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Lise-Marie Donnio ◽  
Anna Lagarou ◽  
Gabrielle Sueur ◽  
Pierre-Olivier Mari ◽  
Giuseppina Giglia-Mari
Keyword(s):  
Dna Repair ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Uv Irradiation ◽  
Dna Lesions ◽  
Premature Aging ◽  
Cyclin Dependent Kinase ◽  
Cyclin T1 ◽  
Group B ◽  
Transcription Coupled Repair

ABSTRACT DNA lesions block cellular processes such as transcription, inducing apoptosis, tissue failures, and premature aging. To counteract the deleterious effects of DNA damage, cells are equipped with various DNA repair pathways. Transcription-coupled repair specifically removes helix-distorting DNA adducts in a coordinated multistep process. This process has been extensively studied; however, once the repair reaction is accomplished, little is known about how transcription restarts. In this study, we show that, after UV irradiation, the cyclin-dependent kinase 9 (CDK9)/cyclin T1 kinase unit is specifically released from the HEXIM1 complex and that this released fraction is degraded in the absence of the Cockayne syndrome group B protein (CSB). We determine that UV irradiation induces a specific Ser2 phosphorylation of the RNA polymerase II and that this phosphorylation is CSB dependent. Surprisingly, CDK9 is not responsible for this phosphorylation but instead might play a nonenzymatic role in transcription restart after DNA repair.

Xeroderma Pigmentosum and Cockayne Syndrome

PEDIATRICS ◽  
1978 ◽  
Vol 61 (4) ◽  
pp. 675-676
Author(s):  
J. M. Dupuy ◽  
D. Lafforet
Keyword(s):  
Dna Repair ◽  
Xeroderma Pigmentosum ◽  
Thymidine Incorporation ◽  
Uv Light ◽  
Tritiated Thymidine ◽  
Clinical Manifestations ◽  
Light Sensitivity ◽  
Cockayne Syndrome ◽  
Uv Light Irradiation ◽  
Clinical Profiles

In the August 1977 issue of Pediatrics (60:135, 1977), R. D. Schmickel et al. demonstrated an increased ultraviolet (UV) light sensitivity and normal DNA repair by Cockayne cells. In 1974 we published the case of a 10-year-old girl who presented clinical manifestations of both Cockayne syndrome and xeroderma pigmentosum.1 Since the cells of this patient were DNA repair-deficient, we postulated that the various clinical profiles observed in xeroderma pigmen-Ultraviolet (UV) light-induced tritiated thymidine incorporation into 106 lymphocytes from normal donors and patients during five hours of incubation after UV light irradiation (30 and 300 ergs/sq mm). See image in the PDF file

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.

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