XPA xeroderma pigmentosum, complementation group A)

2001-02-01   Anne Stary , Alain Sarasin 

Laboratory of Genetic Instability, Cancer, UPR2169 CNRS, Institut de Recherches sur le Cancer, 7, rue guy Moquet, BP 8, 94801 VILLEJUIF, France

Identity

HGNC
LOCATION
9q22.33
LOCUSID
ALIAS
XP1,XPAC
FUSION GENES

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.

Homology

Xpac (FlyBase ID) ; Xpa (MGI)

Mutations

Germinal

13 nucleotide substitutions and 5 small insertion/deletion in patients

Implicated in

Entity name
xeroderma pigmentosum XPA
Disease
predisposition to skin cancer: early skin tumours ( basal cell carcinoma, squamous cell carcinoma and melanoma); early internal tumours

Bibliography

Pubmed IDLast YearTitleAuthors
76977161995Mammalian DNA nucleotide excision repair reconstituted with purified protein components.Aboussekhra A et al
106735062000Nucleotide 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
75262001994The XPA protein is a zinc metalloprotein with an ability to recognize various kinds of DNA damage.Asahina H et al
108734652000Stable binding of human XPC complex to irradiated DNA confers strong discrimination for damaged sites.Batty D et al
106750302000Damage recognition in nucleotide excision repair of DNA.Batty DP et al
90448291997Relative susceptibilities of XPA knockout mice and their heterozygous and wild-type littermates to UVB-induced skin cancer.Berg RJ et al
91953371997Human 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
93904121997Human 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
108620892000Identification of four single nucleotide polymorphisms in DNA repair genes: XPA and XPB (ERCC3) in Polish population.Butkiewicz D et al
77679571995Development of a new easy complementation assay for DNA repair deficient human syndromes using cloned repair genes.Carreau M et al
104035181999A novel function of emodin: enhancement of the nucleotide excision repair of UV- and cisplatin-induced DNA damage in human cells.Chang LC et al
104472541999A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy.Cleaver JE et al
92023161997Loss 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
96996341998Solution structure of the DNA- and RPA-binding domain of the human repair factor XPA.Ikegami T et al
104130201999Neurodegeneration in hereditary nucleotide repair disorders.Itoh M et al
97537351998Mutational analysis of a function of xeroderma pigmentosum group A (XPA) protein in strand-specific DNA repair.Kobayashi T et al
79627831994Siblings with xeroderma pigmentosum complementation group A with different skin cancer development: importance of sun protection at an early age.Kondoh M et al
85386521996Identification of a damaged-DNA binding domain of the XPA protein.Kuraoka I et al
90424151997Quantification of XPA gene expression levels in human and mouse cell lines by competitive RT-PCR.Layher SK et al
103404741999Functional studies on the interaction between human replication protein A and Xeroderma pigmentosum group A complementing protein (XPA).Lee BE et al
76146891995Expression 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
96985411998Interactions of the transcription/DNA repair factor TFIIH and XP repair proteins with DNA lesions in a cell-free repair assay.Li RY et al
78761671995DNA repair protein XPA binds replication protein A (RPA).Matsuda T et al
109462332000Three-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
109445292000XAB2, a novel tetratricopeptide repeat protein involved in transcription-coupled DNA repair and transcription.Nakatsu Y et al
81056861993High 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
92872941997DNA damage recognition by XPA protein promotes efficient recruitment of transcription factor II H.Nocentini S et al
78762631995The 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
81971751994Formation of a ternary complex by human XPA, ERCC1, and ERCC4(XPF) excision repair proteins.Park CH et al
89728581996Sequential binding of DNA repair proteins RPA and ERCC1 to XPA in vitro.Saijo M et al
85954291995Two novel splicing mutations in the XPA gene in patients with group A xeroderma pigmentosum.Satokata I et al
96712711998Distribution 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
94850151998Strand specificity and absence of hot spots for p53 mutations in ultraviolet B-induced skin tumors of XPA-deficient mice.Takeuchi S et al
103734921999Order of assembly of human DNA repair excision nuclease.Wakasugi M et al
94153141997Retrovirus-mediated gene transfer corrects DNA repair defect of xeroderma pigmentosum cells of complementation groups A, B and C.Zeng L et al
95537211998Retrovirus-mediated DNA repair gene transfer into xeroderma pigmentosum cells: perspectives for a gene therapy.Zeng L et al
104166151999Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition.de Boer J et al
91809281997Spontaneous liver tumors and benzo[a]pyrene-induced lymphomas in XPA-deficient mice.de Vries A et al
108381412000Mutagenesis 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 IDTranscript IDUniprot
ENSG00000136936ENST00000375128P23025
ENSG00000136936ENST00000462523F2Z2T2

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Nucleotide excision repairKEGGko03420
Nucleotide excision repairKEGGhsa03420
DNA RepairREACTOMER-HSA-73894
Nucleotide Excision RepairREACTOMER-HSA-5696398
Global Genome Nucleotide Excision Repair (GG-NER)REACTOMER-HSA-5696399
Formation of Incision Complex in GG-NERREACTOMER-HSA-5696395
Dual Incision in GG-NERREACTOMER-HSA-5696400
Transcription-Coupled Nucleotide Excision Repair (TC-NER)REACTOMER-HSA-6781827
Formation of TC-NER Pre-Incision ComplexREACTOMER-HSA-6781823
Dual incision in TC-NERREACTOMER-HSA-6782135
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164713176Platinum compoundsChemicalClinicalAnnotationassociatedPD25069034
PA443622Carcinoma, Non-Small-Cell LungDiseaseClinicalAnnotationassociatedPD25069034

References

Pubmed IDYearTitleCitations
161952372006Polymorphisms of DNA repair genes and risk of non-small cell lung cancer.112
203048032010Circadian control of XPA and excision repair of cisplatin-DNA damage by cryptochrome and HERC2 ubiquitin ligase.82
152137132004A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer.75
206708932010SIRT1 regulates UV-induced DNA repair through deacetylating XPA.75
191163882009A field synopsis on low-penetrance variants in DNA repair genes and cancer susceptibility.63
150952992004Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines.60
175315252007Polymorphisms in base-excision repair and nucleotide-excision repair genes in relation to lung cancer risk.55
119720362002Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions.52
128971462003Xeroderma pigmentosum group A protein loads as a separate factor onto DNA lesions.52
153334652004Specific combinations of DNA repair gene variants and increased risk for non-small cell lung cancer.50

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