XPA xeroderma pigmentosum, complementation group A)
2001-02-01 Anne Stary , Alain Sarasin AffiliationLaboratory of Genetic Instability, Cancer, UPR2169 CNRS, Institut de Recherches sur le Cancer, 7, rue guy Moquet, BP 8, 94801 VILLEJUIF, France
DNA/RNA
Description
human xeroderma pigmentosum group A 25kbp, six exons, 2 polyadenylation signals
Transcription
1377 b mRNA; suggestion of 1 major transcript; promoter G+C rich (73%); one CAAT box and no TATA box.
Proteins
Description
273 amino acids, 31 kDa. DNA excision repair protein. The functional domain for damaged DNA recognition contains a zinc-finger motif with 4 cysteine residues : Cys-X2-Cys-X17-Cys-X2-Cys motif and a glutamic acid cluster encoded by Exon 2. The nuclear localization signal is located in Exon 1.
Expression
ubiquitous
Localisation
nuclear
Function
Initiates DNA repair by binding to damaged sites with various affinities, depending upon the chemical structure of the lesion
Two proteins have been identified and implicated in (one of) the first steps of Nucleotide Excision Repair (NER), i.e. the recognition of lesions in the DNA: the XPA gene product and the XPC gene product. Cells from XPA patients are extremely sensitive to UV and have very low nucleotide excision repair activity. In vitro the XPA protein binds preferentially to damaged DNA compared to nondamaged DNA. The XPA protein binds to replication protein A (RPA) which enhances the affinity of XPA for damaged DNA and is essential for NER. The XPA protein has been shown to bind to ERCC1 and TFIIH. It is possible that the complex XPA/RPA may tell to the repair machinery which strand contained the damage and therefore should be eliminated.
Two proteins have been identified and implicated in (one of) the first steps of Nucleotide Excision Repair (NER), i.e. the recognition of lesions in the DNA: the XPA gene product and the XPC gene product. Cells from XPA patients are extremely sensitive to UV and have very low nucleotide excision repair activity. In vitro the XPA protein binds preferentially to damaged DNA compared to nondamaged DNA. The XPA protein binds to replication protein A (RPA) which enhances the affinity of XPA for damaged DNA and is essential for NER. The XPA protein has been shown to bind to ERCC1 and TFIIH. It is possible that the complex XPA/RPA may tell to the repair machinery which strand contained the damage and therefore should be eliminated.
Homology
Xpac (FlyBase ID) ; Xpa (MGI)
Mutations
Germinal
13 nucleotide substitutions and 5 small insertion/deletion in patients
Implicated in
Entity name
Disease
predisposition to skin cancer: early skin tumours ( basal cell carcinoma, squamous cell carcinoma and melanoma); early internal tumours
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 7697716 | 1995 | Mammalian DNA nucleotide excision repair reconstituted with purified protein components. | Aboussekhra A et al |
| 10673506 | 2000 | Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK. | Araújo SJ et al |
| 7526200 | 1994 | The XPA protein is a zinc metalloprotein with an ability to recognize various kinds of DNA damage. | Asahina H et al |
| 10873465 | 2000 | Stable binding of human XPC complex to irradiated DNA confers strong discrimination for damaged sites. | Batty D et al |
| 10675030 | 2000 | Damage recognition in nucleotide excision repair of DNA. | Batty DP et al |
| 9044829 | 1997 | Relative susceptibilities of XPA knockout mice and their heterozygous and wild-type littermates to UVB-induced skin cancer. | Berg RJ et al |
| 9195337 | 1997 | Human nucleotide excision repair protein XPA: 1H NMR and CD solution studies of a synthetic peptide fragment corresponding to the zinc-binding domain (101-141). | Buchko GW et al |
| 9390412 | 1997 | Human nucleotide excision repair protein XPA: expression and NMR backbone assignments of the 14.7 kDa minimal damaged DNA binding domain (Met98-Phe219). | Buchko GW et al |
| 10862089 | 2000 | Identification of four single nucleotide polymorphisms in DNA repair genes: XPA and XPB (ERCC3) in Polish population. | Butkiewicz D et al |
| 7767957 | 1995 | Development of a new easy complementation assay for DNA repair deficient human syndromes using cloned repair genes. | Carreau M et al |
| 10403518 | 1999 | A novel function of emodin: enhancement of the nucleotide excision repair of UV- and cisplatin-induced DNA damage in human cells. | Chang LC et al |
| 10447254 | 1999 | A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. | Cleaver JE et al |
| 9202316 | 1997 | Loss of the xeroderma pigmentosum group A gene (XPA) enhances apoptosis of cultured cerebellar neurons induced by UV but not by low-K+ medium. | Enokido Y et al |
| 9699634 | 1998 | Solution structure of the DNA- and RPA-binding domain of the human repair factor XPA. | Ikegami T et al |
| 10413020 | 1999 | Neurodegeneration in hereditary nucleotide repair disorders. | Itoh M et al |
| 9753735 | 1998 | Mutational analysis of a function of xeroderma pigmentosum group A (XPA) protein in strand-specific DNA repair. | Kobayashi T et al |
| 7962783 | 1994 | Siblings with xeroderma pigmentosum complementation group A with different skin cancer development: importance of sun protection at an early age. | Kondoh M et al |
| 8538652 | 1996 | Identification of a damaged-DNA binding domain of the XPA protein. | Kuraoka I et al |
| 9042415 | 1997 | Quantification of XPA gene expression levels in human and mouse cell lines by competitive RT-PCR. | Layher SK et al |
| 10340474 | 1999 | Functional studies on the interaction between human replication protein A and Xeroderma pigmentosum group A complementing protein (XPA). | Lee BE et al |
| 7614689 | 1995 | Expression of a transfected DNA repair gene (XPA) in xeroderma pigmentosum group A cells restores normal DNA repair and mutagenesis of UV-treated plasmids. | Levy DD et al |
| 9698541 | 1998 | Interactions of the transcription/DNA repair factor TFIIH and XP repair proteins with DNA lesions in a cell-free repair assay. | Li RY et al |
| 7876167 | 1995 | DNA repair protein XPA binds replication protein A (RPA). | Matsuda T et al |
| 10946233 | 2000 | Three-dimensional structural views of damaged-DNA recognition: T4 endonuclease V, E. coli Vsr protein, and human nucleotide excision repair factor XPA. | Morikawa K et al |
| 10944529 | 2000 | XAB2, a novel tetratricopeptide repeat protein involved in transcription-coupled DNA repair and transcription. | Nakatsu Y et al |
| 8105686 | 1993 | High prevalence of the point mutation in exon 6 of the xeroderma pigmentosum group A-complementing (XPAC) gene in xeroderma pigmentosum group A patients in Tunisia. | Nishigori C et al |
| 9287294 | 1997 | DNA damage recognition by XPA protein promotes efficient recruitment of transcription factor II H. | Nocentini S et al |
| 7876263 | 1995 | The general transcription-repair factor TFIIH is recruited to the excision repair complex by the XPA protein independent of the TFIIE transcription factor. | Park CH et al |
| 8197175 | 1994 | Formation of a ternary complex by human XPA, ERCC1, and ERCC4(XPF) excision repair proteins. | Park CH et al |
| 8972858 | 1996 | Sequential binding of DNA repair proteins RPA and ERCC1 to XPA in vitro. | Saijo M et al |
| 8595429 | 1995 | Two novel splicing mutations in the XPA gene in patients with group A xeroderma pigmentosum. | Satokata I et al |
| 9671271 | 1998 | Distribution of mutations in the human xeroderma pigmentosum group A gene and their relationships to the functional regions of the DNA damage recognition protein. | States JC et al |
| 9485015 | 1998 | Strand specificity and absence of hot spots for p53 mutations in ultraviolet B-induced skin tumors of XPA-deficient mice. | Takeuchi S et al |
| 10373492 | 1999 | Order of assembly of human DNA repair excision nuclease. | Wakasugi M et al |
| 9415314 | 1997 | Retrovirus-mediated gene transfer corrects DNA repair defect of xeroderma pigmentosum cells of complementation groups A, B and C. | Zeng L et al |
| 9553721 | 1998 | Retrovirus-mediated DNA repair gene transfer into xeroderma pigmentosum cells: perspectives for a gene therapy. | Zeng L et al |
| 10416615 | 1999 | Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition. | de Boer J et al |
| 9180928 | 1997 | Spontaneous liver tumors and benzo[a]pyrene-induced lymphomas in XPA-deficient mice. | de Vries A et al |
| 10838141 | 2000 | Mutagenesis and carcinogenesis in nucleotide excision repair-deficient XPA knock out mice. | van Steeg H et al |
Other Information
Locus ID:
NCBI: 7507
MIM: 611153
HGNC: 12814
Ensembl: ENSG00000136936
Variants:
dbSNP: 7507
ClinVar: 7507
TCGA: ENSG00000136936
COSMIC: XPA
RNA/Proteins
| Gene ID | Transcript ID | Uniprot |
|---|---|---|
| ENSG00000136936 | ENST00000375128 | P23025 |
| ENSG00000136936 | ENST00000462523 | F2Z2T2 |
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA164713176 | Platinum compounds | Chemical | ClinicalAnnotation | associated | PD | 25069034 | |
| PA443622 | Carcinoma, Non-Small-Cell Lung | Disease | ClinicalAnnotation | associated | PD | 25069034 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 36893274 | 2023 | A disease-associated XPA allele interferes with TFIIH binding and primarily affects transcription-coupled nucleotide excision repair. | 2 |
| 37076618 | 2023 | Lesion recognition by XPC, TFIIH and XPA in DNA excision repair. | 10 |
| 37510255 | 2023 | A Significant Increasing Risk Association between Cigarette Smoking and XPA and XPC Genes Polymorphisms. | 0 |
| 36893274 | 2023 | A disease-associated XPA allele interferes with TFIIH binding and primarily affects transcription-coupled nucleotide excision repair. | 2 |
| 37076618 | 2023 | Lesion recognition by XPC, TFIIH and XPA in DNA excision repair. | 10 |
| 37510255 | 2023 | A Significant Increasing Risk Association between Cigarette Smoking and XPA and XPC Genes Polymorphisms. | 0 |
| 34883264 | 2022 | XPA is susceptible to proteolytic cleavage by cathepsin L during lysis of quiescent cells. | 2 |
| 35084844 | 2022 | Probing Protein-DNA Conformational Dynamics in DNA Damage Recognition: Xeroderma Pigmentosum Group A Stabilizes the Damaged DNA-RPA14 Complex by Controlling Conformational Fluctuation Dynamics. | 0 |
| 35216341 | 2022 | Nucleotide Excision Repair Pathway Activity Is Inhibited by Airborne Particulate Matter (PM(10)) through XPA Deregulation in Lung Epithelial Cells. | 1 |
| 35536165 | 2022 | XPA Enhances Temozolomide Resistance of Glioblastoma Cells by Promoting Nucleotide Excision Repair. | 3 |
| 36232946 | 2022 | Homozygous CRISPR/Cas9 Knockout Generated a Novel Functionally Active Exon 1 Skipping XPA Variant in Melanoma Cells. | 1 |
| 34883264 | 2022 | XPA is susceptible to proteolytic cleavage by cathepsin L during lysis of quiescent cells. | 2 |
| 35084844 | 2022 | Probing Protein-DNA Conformational Dynamics in DNA Damage Recognition: Xeroderma Pigmentosum Group A Stabilizes the Damaged DNA-RPA14 Complex by Controlling Conformational Fluctuation Dynamics. | 0 |
| 35216341 | 2022 | Nucleotide Excision Repair Pathway Activity Is Inhibited by Airborne Particulate Matter (PM(10)) through XPA Deregulation in Lung Epithelial Cells. | 1 |
| 35536165 | 2022 | XPA Enhances Temozolomide Resistance of Glioblastoma Cells by Promoting Nucleotide Excision Repair. | 3 |
Citation
Anne Stary ; Alain Sarasin
XPA xeroderma pigmentosum, complementation group A)
Atlas Genet Cytogenet Oncol Haematol. 2001-02-01
Online version: http://atlasgeneticsoncology.org/gene/104/xpa
