scholarly journals Xeroderma Pigmentosum: General Aspects and Management

2021 ◽  
Vol 11 (11) ◽  
pp. 1146
Author(s):  
Monica Piccione ◽  
Anna Belloni Fortina ◽  
Giulia Ferri ◽  
Gloria Andolina ◽  
Lorenzo Beretta ◽  
...  
Keyword(s):  
Xeroderma Pigmentosum ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Clinical Signs ◽  
Severe Form ◽  
Genetic Syndrome ◽  
Advantages And Disadvantages ◽  
Skin Cancers ◽  
Extreme Sensitivity ◽  
General Aspects

Xeroderma Pigmentosum (XP) is a rare genetic syndrome with a defective DNA nucleotide excision repair. It is characterized by (i) an extreme sensitivity to ultraviolet (UV)-induced damages in the skin and eyes; (ii) high risk to develop multiple skin tumours; and (iii) neurologic alterations in the most severe form. To date, the management of XP patients consists of (i) early diagnosis; (ii) a long-life protection from ultraviolet radiation, including avoidance of unnecessary UV exposure, wearing UV blocking clothing, and use of topical sunscreens; and (iii) surgical resections of skin cancers. No curative treatment is available at present. Thus, in the last decade, in order to prevent or delay the progression of the clinical signs of XP, numerous strategies have been proposed and tested, in some cases, with adverse effects. The present review provides an overview of the molecular mechanisms featuring the development of XP and highlights both advantages and disadvantages of the clinical approaches developed throughout the years. The intention of the authors is to sensitize scientists to the crucial aspects of the pathology that could be differently targeted. In this context, the exploration of the process underlining the conception of liposomal nanocarriers is reported to focus the attention on the potentialities of liposomal technology to optimize the administration of chemoprotective agents in XP patients.

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.

scholarly journals Molecular mechanisms of xeroderma pigmentosum (XP) proteins

2016 ◽  
Vol 49 ◽  
Author(s):  
Sandra C. Koch ◽  
Nina Simon ◽  
Charlotte Ebert ◽  
Thomas Carell
Keyword(s):  
Dna Repair ◽  
Substrate Specificity ◽  
Xeroderma Pigmentosum ◽  
Molecular Mechanisms ◽  
Structural Information ◽  
Excision Repair ◽  
Dna Lesions ◽  
Environmental Chemicals ◽  
Dna Damages ◽  
Broad Substrate Specificity

AbstractNucleotide excision repair (NER) is a highly versatile and efficient DNA repair process, which is responsible for the removal of a large number of structurally diverse DNA lesions. Its extreme broad substrate specificity ranges from DNA damages formed upon exposure to ultraviolet radiation to numerous bulky DNA adducts induced by mutagenic environmental chemicals and cytotoxic drugs used in chemotherapy. Defective NER leads to serious diseases, such as xeroderma pigmentosum (XP). Eight XP complementation groups are known of which seven (XPA–XPG) are caused by mutations in genes involved in the NER process. The eighth gene, XPV, codes for the DNA polymerase ɳ, which replicates through DNA lesions in a process called translesion synthesis (TLS). Over the past decade, detailed structural information of these DNA repair proteins involved in eukaryotic NER and TLS have emerged. These structures allow us now to understand the molecular mechanism of the NER and TLS processes in quite some detail and we have begun to understand the broad substrate specificity of NER. In this review, we aim to highlight recent advances in the process of damage recognition and repair as well as damage tolerance by the XP proteins.

scholarly journals Daily Lifestyle and Cutaneous Malignancies

2021 ◽  
Vol 22 (10) ◽  
pp. 5227
Author(s):  
Yu Sawada ◽  
Motonobu Nakamura
Keyword(s):  
Cell Carcinoma ◽  
Molecular Mechanisms ◽  
Skin Diseases ◽  
Human Life ◽  
Lifestyle Factors ◽  
Merkel Cell ◽  
Fundamental Part ◽  
Skin Cancers ◽  
Beneficial Impact ◽  
The Relationship

Daily lifestyle is a fundamental part of human life and its influence accumulates daily in the human body. We observe that a good daily lifestyle has a beneficial impact on our health; however, the actual effects of individual daily lifestyle factors on human skin diseases, especially skin cancers, have not been summarized. In this review, we focused on the influence of daily lifestyle on the development of skin cancer and described the detailed molecular mechanisms of the development or regulation of cutaneous malignancies. Several daily lifestyle factors, such as circadian rhythm disruption, smoking, alcohol, fatty acids, dietary fiber, obesity, and ultraviolet light, are known to be associated with the risk of cutaneous malignancies, malignant melanoma, squamous cell carcinoma, basal cell carcinoma, and Merkel cell carcinoma. Although the influence of some daily lifestyles on the risk of skin cancers is controversial, this review provides us a better understanding of the relationship between daily lifestyle factors and skin cancers.

scholarly journals Xeroderma Pigmentosum Diagnosis Using a Flow Cytometry-Based Nucleotide Excision Repair Assay

2018 ◽  
Vol 138 (2) ◽  
pp. 467-470 ◽  
Author(s):  
Eiji Nakano ◽  
Seiji Takeuchi ◽  
Ryusuke Ono ◽  
Mariko Tsujimoto ◽  
Taro Masaki ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Nucleotide Excision Repair ◽  
Xeroderma Pigmentosum ◽  
Excision Repair ◽  
Nucleotide Excision

Xeroderma pigmentosum complementation group C cells remove pyrimidine dimers selectively from the transcribed strand of active genes

1991 ◽  
Vol 11 (8) ◽  
pp. 4128-4134
Author(s):  
J Venema ◽  
A van Hoffen ◽  
V Karcagi ◽  
A T Natarajan ◽  
A A van Zeeland ◽  
...  
Keyword(s):  
Xeroderma Pigmentosum ◽  
Mammalian Cells ◽  
Excision Repair ◽  
Complementation Group ◽  
C Cells ◽  
Dhfr Gene ◽  
Normal Cells ◽  
Pyrimidine Dimers ◽  
Normal Human ◽  
Active Genes

We have measured the removal of UV-induced pyrimidine dimers from DNA fragments of the adenosine deaminase (ADA) and dihydrofolate reductase (DHFR) genes in primary normal human and xeroderma pigmentosum complementation group C (XP-C) cells. Using strand-specific probes, we show that in normal cells, preferential repair of the 5' part of the ADA gene is due to the rapid and efficient repair of the transcribed strand. Within 8 h after irradiation with UV at 10 J m-2, 70% of the pyrimidine dimers in this strand are removed. The nontranscribed strand is repaired at a much slower rate, with 30% dimers removed after 8 h. Repair of the transcribed strand in XP-C cells occurs at a rate indistinguishable from that in normal cells, but the nontranscribed strand is not repaired significantly in these cells. Similar results were obtained for the DHFR gene. In the 3' part of the ADA gene, however, both normal and XP-C cells perform fast and efficient repair of either strand, which is likely to be caused by the presence of transcription units on both strands. The factor defective in XP-C cells is apparently involved in the processing of DNA damage in inactive parts of the genome, including nontranscribed strands of active genes. These findings have important implications for the understanding of the mechanism of UV-induced excision repair and mutagenesis in mammalian cells.

Xeroderma pigmentosum Variant Associated with Multiple Skin Cancers and a Lung Cancer

Dermatology ◽  
1992 ◽  
Vol 184 (3) ◽  
pp. 177-181 ◽  
Author(s):  
A. Mamada ◽  
K. Miura ◽  
K. Tsunoda ◽  
I. Hirose ◽  
M. Furuya ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Xeroderma Pigmentosum ◽  
Skin Cancers

scholarly journals Molecular Mechanisms of the Whole DNA Repair System: A Comparison of Bacterial and Eukaryotic Systems

2010 ◽  
Vol 2010 ◽  
pp. 1-32 ◽  
Author(s):  
Rihito Morita ◽  
Shuhei Nakane ◽  
Atsuhiro Shimada ◽  
Masao Inoue ◽  
Hitoshi Iino ◽  
...  
Keyword(s):  
Dna Repair ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Thermus Thermophilus ◽  
Repair System ◽  
System A ◽  
Recombination Repair ◽  
Repair Mechanisms ◽  
Repair Pathways ◽  
Base Excision

DNA is subjected to many endogenous and exogenous damages. All organisms have developed a complex network of DNA repair mechanisms. A variety of different DNA repair pathways have been reported: direct reversal, base excision repair, nucleotide excision repair, mismatch repair, and recombination repair pathways. Recent studies of the fundamental mechanisms for DNA repair processes have revealed a complexity beyond that initially expected, with inter- and intrapathway complementation as well as functional interactions between proteins involved in repair pathways. In this paper we give a broad overview of the whole DNA repair system and focus on the molecular basis of the repair machineries, particularly inThermus thermophilusHB8.

scholarly journals Molecular mechanisms associated with clustered lesion-induced impairment of 8-oxoG recognition by the human glycosylase OGG1

2021 ◽  
Author(s):  
Tao Jiang ◽  
Antonio MONARI ◽  
Elise Dumont ◽  
Emmanuelle Bignon
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Excision Repair ◽  
Structural Features ◽  
Repair Pathway ◽  
Dna Lesion ◽  
Damage Response ◽  
Base Excision ◽  
Structural Signature ◽  
Dynamics Simulations

The 8-oxo-7,8-dihydroguanine, referred to as 8-oxoG, is a highly mutagenic DNA lesion that can provoke the appearance of mismatches if it escapes the DNA Damage Response. The specific recognition of its structural signature by the hOGG1 glycosylase is the first step along the Base Excision Repair pathway, that ensures the integrity of the genome by preventing the emergence of mutations. 8-oxoG formation, structural features and repair have been the matter of extensive research and more recently this active field of research expended to the more complicated case of 8-oxoG within clustered lesions. Indeed, the presence of a second lesion within 1 or 2 helix turns can dramatically impact the repair yields of 8-oxoG by glycosylases. In this work, we use mu-range molecular dynamics simulations and machine learning-based post-analysis to explore the molecular mechanisms associated with the recognition of 8-oxoG by hOGG1 when embedded in a multiple lesions site with a mismatch in 5' or 3'. We delineate the stiffening of the DNA-protein interactions upon the presence of the mismatches, and rationalize the much lower repair yields reported with a 5' mismatch by describing the perturbation of 8-oxoG structural features upon addition of an adjacent lesion.

Sign in / Sign up

Export Citation Format

Share Document