XPA xeroderma pigmentosum, complementation group A)

2001-02-01 Anne Stary , Alain Sarasin Affiliation

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

Identity

HGNC

XPA

LOCATION

9q22.33

LOCUSID

7507

ALIAS

XP1,XPAC

FUSION GENES

Show Gene Fusions

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

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)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Nucleotide excision repair	KEGG	ko03420
Nucleotide excision repair	KEGG	hsa03420
DNA Repair	REACTOME	R-HSA-73894
Nucleotide Excision Repair	REACTOME	R-HSA-5696398
Global Genome Nucleotide Excision Repair (GG-NER)	REACTOME	R-HSA-5696399
Formation of Incision Complex in GG-NER	REACTOME	R-HSA-5696395
Dual Incision in GG-NER	REACTOME	R-HSA-5696400
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	REACTOME	R-HSA-6781827
Formation of TC-NER Pre-Incision Complex	REACTOME	R-HSA-6781823
Dual incision in TC-NER	REACTOME	R-HSA-6782135
Platinum drug resistance	KEGG	ko01524
Platinum drug resistance	KEGG	hsa01524

Protein levels (Protein atlas)

Not detected

Low

Medium

High

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