scholarly journals Hereditary Disorders with Defective Repair of UV-Induced DNA Damage

2013 ◽  
Vol 4 ◽  
pp. JCM.S10730 ◽  
Author(s):  
Shinichi Moriwaki
Keyword(s):  
Dna Damage ◽  
Xeroderma Pigmentosum ◽  
Excision Repair ◽  
Genetic Disorder ◽  
Symptomatic Treatment ◽  
Premature Aging ◽  
Genetic Defects ◽  
Nucleotide Excision ◽  
Hereditary Disorders ◽  
Human Genetic Disorder

Nucleotide excision repair (NER) is an essential system for correcting ultraviolet (UV)–-induced DNA damage. Lesions remaining in DNA due to reduced capacity of NER may result in cellular death, premature aging, mutagenesis and carcinogenesis of the skin. So, NER is an important protection against these changes. There are three representative genodermatoses resulting from genetic defects in NER: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). In Japan, CS is similarly rare but XP is more common and TTD is less common compared to Western countries. In 1998, we established the system for the diagnosis of these disorders and we have been performing DNA repair and genetic analysis for more than 400 samples since then. At present, there is no cure for any human genetic disorder. Early diagnosis and symptomatic treatment of neurological, ocular and dermatological abnormalities should contribute to prolonging life and elevating QOL in patients.

scholarly journals Xeroderma Pigmentosum: Gene Variants and Splice Variants

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1173
Author(s):  
Marie Christine Martens ◽  
Steffen Emmert ◽  
Lars Boeckmann
Keyword(s):  
Dna Damage ◽  
Xeroderma Pigmentosum ◽  
Splice Variants ◽  
Excision Repair ◽  
Genetic Disorder ◽  
Cyclobutane Pyrimidine Dimers ◽  
Pyrimidine Dimers ◽  
Damage Repair ◽  
Nucleotide Excision ◽  
Functional Relevance

The nucleotide excision repair (NER) is essential for the repair of ultraviolet (UV)-induced DNA damage, such as cyclobutane pyrimidine dimers (CPDs) and 6,4-pyrimidine-pyrimidone dimers (6,4-PPs). Alterations in genes of the NER can lead to DNA damage repair disorders such as Xeroderma pigmentosum (XP). XP is a rare autosomal recessive genetic disorder associated with UV-sensitivity and early onset of skin cancer. Recently, extensive research has been conducted on the functional relevance of splice variants and their relation to cancer. Here, we focus on the functional relevance of alternative splice variants of XP genes.

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 DDB2 Complex-Mediated Ubiquitylation around DNA Damage Is Oppositely Regulated by XPC and Ku and Contributes to the Recruitment of XPA

2010 ◽  
Vol 30 (11) ◽  
pp. 2708-2723 ◽  
Author(s):  
Arato Takedachi ◽  
Masafumi Saijo ◽  
Kiyoji Tanaka
Keyword(s):  
Dna Damage ◽  
Ubiquitin Ligase ◽  
Xeroderma Pigmentosum ◽  
Excision Repair ◽  
Dna Binding Protein ◽  
Negative Regulator ◽  
Ubiquitin Ligase Activity ◽  
Nucleotide Excision ◽  
Cullin 4A ◽  
Damaged Dna

ABSTRACT UV-damaged-DNA-binding protein (UV-DDB) is a heterodimer comprised of DDB1 and DDB2 and integrated in a complex that includes a ubiquitin ligase component, cullin 4A, and Roc1. Here we show that the ubiquitin ligase activity of the DDB2 complex is required for efficient global genome nucleotide excision repair (GG-NER) in chromatin. Mutant DDB2 proteins derived from xeroderma pigmentosum group E patients are not able to mediate ubiquitylation around damaged sites in chromatin. We also found that CSN, a negative regulator of cullin-based ubiquitin ligases, dissociates from the DDB2 complex when the complex binds to damaged DNA and that XPC and Ku oppositely regulate the ubiquitin ligase activity, especially around damaged sites. Furthermore, the DDB2 complex-mediated ubiquitylation plays a role in recruiting XPA to damaged sites. These findings shed some light on the early stages of GG-NER.

scholarly journals Case Report: Identification of Novel Variants in ERCC4 and DDB2 Genes in Two Tunisian Patients With Atypical Xeroderma Pigmentosum Phenotype

2021 ◽  
Vol 12 ◽  
Author(s):  
Imen Nabouli ◽  
Asma Chikhaoui ◽  
Houcemeddine Othman ◽  
Sahar Elouej ◽  
Meriem Jones ◽  
...  
Keyword(s):  
Xeroderma Pigmentosum ◽  
Excision Repair ◽  
Clinical Investigation ◽  
Genetic Disorder ◽  
Diagnostic Testing ◽  
Gene Sequencing ◽  
Genetic Defects ◽  
Repair System ◽  
Novel Variants ◽  
Targeted Gene Sequencing

Xeroderma Pigmentosum (XP) is a rare genetic disorder affecting the nucleotide excision repair system (NER). It is characterized by an extreme sensitivity to sunlight that induces cutaneous disorders such as severe sunburn, freckling and cancers. In Tunisia, six complementation groups have been already identified. However, the genetic etiology remains unknown for several patients. In this study, we investigated clinical characteristics and genetic defects in two families with atypical phenotypes originating from the central region in Tunisia. Clinical investigation revealed mild cutaneous features in two patients who develop multiple skin cancers at later ages, with no neurological disorders. Targeted gene sequencing revealed that they carried novel variants. A homozygous variation in the ERCC4 gene c.1762G>T, p.V588F, detected in patient XP21. As for patient XP134, he carried two homozygous mutations in the DDB2 gene c.613T>C, p.C205R and c.618C>A, p.S206R. Structural modeling of the protein predicted the identified ERCC4 variant to mildly affect protein stability without affecting its functional domains. As for the case of DDB2 double mutant, the second variation seems to cause a mild effect on the protein structure unlike the first variation which does not seem to have an effect on it. This study contributes to further characterize the mutation spectrum of XP in Tunisian families. Targeted gene sequencing accelerated the identification of rare unexpected genetic defects for diagnostic testing and genetic counseling.

scholarly journals An Xpb Mouse Model for Combined Xeroderma Pigmentosum and Cockayne Syndrome Reveals Progeroid Features upon Further Attenuation of DNA Repair

2008 ◽  
Vol 29 (5) ◽  
pp. 1276-1290 ◽  
Author(s):  
Jaan-Olle Andressoo ◽  
Geert Weeda ◽  
Jan de Wit ◽  
James R. Mitchell ◽  
Rudolf B. Beems ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Xeroderma Pigmentosum ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Cockayne Syndrome ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Neonatal Lethality ◽  
Nucleotide Excision

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.

scholarly journals Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients

2009 ◽  
Vol 206 (13) ◽  
pp. 3031-3046 ◽  
Author(s):  
Takahiro Ueda ◽  
Emmanuel Compe ◽  
Philippe Catez ◽  
Kenneth H. Kraemer ◽  
Jean-Marc Egly
Keyword(s):  
Rna Polymerase Ii ◽  
Xeroderma Pigmentosum ◽  
Excision Repair ◽  
Genetic Disorder ◽  
Biochemical Properties ◽  
Null Alleles ◽  
Skin Cancers ◽  
Nucleotide Excision ◽  
Xpd Helicase ◽  
Compound Heterozygotes

Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in the rare recessive genetic disorder xeroderma pigmentosum (XP). Many XP patients are compound heterozygotes with a “causative” XPD point mutation R683W and different second mutant alleles, considered “null alleles.” However, there is marked clinical heterogeneity (including presence or absence of skin cancers or neurological degeneration) in these XPD/R683W patients, thus suggesting a contribution of the second allele. Here, we report XP patients carrying XPD/R683W and a second XPD allele either XPD/Q452X, /I455del, or /199insPP. We performed a systematic study of the effect of these XPD mutations on several enzymatic functions of TFIIH and found that each mutation exhibited unique biochemical properties. Although all the mutations inhibited the nucleotide excision repair (NER) by disturbing the XPD helicase function, each of them disrupted specific molecular steps during transcription: XPD/Q452X hindered the transactivation process, XPD/I455del disturbed RNA polymerase II phosphorylation, and XPD/199insPP inhibited kinase activity of the cdk7 subunit of TFIIH. The broad range and severity of clinical features in XP patients arise from a broad set of deficiencies in NER and transcription that result from the combination of mutations found on both XPD alleles.

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