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.

The XPD helicase: XPanDing archaeal XPD structures to get a grip on human DNA repair

2010 ◽  
Vol 391 (7) ◽  
Author(s):  
Stefanie C. Wolski ◽  
Jochen Kuper ◽  
Caroline Kisker
Keyword(s):  
Transcription Initiation ◽  
Xeroderma Pigmentosum ◽  
Excision Repair ◽  
Complementation Group ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Nucleotide Excision ◽  
Xpd Helicase ◽  
Group D

Abstract Xeroderma pigmentosum complementation group D protein (XPD) is an iron-sulfur cluster containing 5′-3′ helicase and, in humans, part of the transcription factor TFIIH. TFIIH is involved in nucleotide excision repair as well as in transcription initiation. Recently, three different groups have reported the structures of archaeal XPDs. All structures revealed a four-domain organization with two RecA-like domains, an Arch domain and an iron-sulfur cluster domain. It was possible to rationalize several of the mutations in the human XPD gene that lead to one of the three severe diseases xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. The different structures are compared and disease-related mutations are discussed.

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 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 XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Andrey A. Yurchenko ◽  
Ismael Padioleau ◽  
Bakhyt T. Matkarimov ◽  
Jean Soulier ◽  
Alain Sarasin ◽  
...  
Keyword(s):  
Excision Repair ◽  
Genetic Disorder ◽  
Fold Increase ◽  
Hematologic Malignancies ◽  
Dna Lesions ◽  
Skin Cancers ◽  
Mutational Pattern ◽  
Increased Risk ◽  
Nucleotide Excision ◽  
Genetic Mechanisms

AbstractRecent studies demonstrated a dramatically increased risk of leukemia in patients with a rare genetic disorder, Xeroderma Pigmentosum group C (XP-C), characterized by constitutive deficiency of global genome nucleotide excision repair (GG-NER). The genetic mechanisms of non-skin cancers in XP-C patients remain unexplored. In this study, we analyze a unique collection of internal XP-C tumor genomes including 6 leukemias and 2 sarcomas. We observe a specific mutational pattern and an average of 25-fold increase of mutation rates in XP-C versus sporadic leukemia which we presume leads to its elevated incidence and early appearance. We describe a strong mutational asymmetry with respect to transcription and the direction of replication in XP-C tumors suggesting association of mutagenesis with bulky purine DNA lesions of probably endogenous origin. These findings suggest existence of a balance between formation and repair of bulky DNA lesions by GG-NER in human body cells which is disrupted in XP-C patients.

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

scholarly journals The crystal structure of human XPG, the xeroderma pigmentosum group G endonuclease, provides insight into nucleotide excision DNA repair

2020 ◽  
Vol 48 (17) ◽  
pp. 9943-9958
Author(s):  
Rocío González-Corrochano ◽  
Federico M Ruiz ◽  
Nicholas M I Taylor ◽  
Sonia Huecas ◽  
Srdja Drakulic ◽  
...  
Keyword(s):  
Dna Binding ◽  
Xeroderma Pigmentosum ◽  
Mutational Analysis ◽  
Excision Repair ◽  
Genetic Diseases ◽  
Complementation Group ◽  
Repair System ◽  
High Plasticity ◽  
Starting Point ◽  
Nucleotide Excision

Abstract Nucleotide excision repair (NER) is an essential pathway to remove bulky lesions affecting one strand of DNA. Defects in components of this repair system are at the ground of genetic diseases such as xeroderma pigmentosum (XP) and Cockayne syndrome (CS). The XP complementation group G (XPG) endonuclease cleaves the damaged DNA strand on the 3′ side of the lesion coordinated with DNA re-synthesis. Here, we determined crystal structures of the XPG nuclease domain in the absence and presence of DNA. The overall fold exhibits similarities to other flap endonucleases but XPG harbors a dynamic helical arch that is uniquely oriented and defines a gateway. DNA binding through a helix-2-turn-helix motif, assisted by one flanking α-helix on each side, shows high plasticity, which is likely relevant for DNA scanning. A positively-charged canyon defined by the hydrophobic wedge and β-pin motifs provides an additional DNA-binding surface. Mutational analysis identifies helical arch residues that play critical roles in XPG function. A model for XPG participation in NER is proposed. Our structures and biochemical data represent a valuable tool to understand the atomic ground of XP and CS, and constitute a starting point for potential therapeutic applications.

Nucleotide Excision Repair in the Three Domains of Life

2011 ◽  
Vol 2 (1) ◽  
Author(s):  
David A Farnell
Keyword(s):  
Dna Repair ◽  
Nucleotide Excision Repair ◽  
Xeroderma Pigmentosum ◽  
Excision Repair ◽  
Human Diseases ◽  
Repair Pathway ◽  
Functional Conservation ◽  
Wide Range ◽  
Nucleotide Excision ◽  
Domains Of Life

Nucleotide excision repair (NER) is a vital DNA repair pathway which acts on a wide range of helix-distorting lesions. The importance of this pathway is highlighted by its functional conservation throughout evolution and by several human diseases, such as xeroderma pigmentosum, which are caused by a defective NER pathway. This review summarizes the NER mechanisms present in all three domains of life: eukaryotes, bacteria, and archaea.

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