ERCC2 (Excision repair cross-complementing rodent repair deficiency, complementation group 2)

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

ERCC2

LOCATION

19q13.32

IMAGE

LEGEND

XPD (19q13) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

LOCUSID

2068

ALIAS

COFS2,EM9,TFIIH,TTD,TTD1,XPD

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

54336 bp; 23 exons

Transcription

2400b mRNA

Proteins

Description

760 amino acids

Expression

ubiquitous

Localisation

nuclear

Function

5-3 ATP-dependent helicase activity involved in DNA excision repair (NER) and as a subunit of the basal transcription factor TFIIH
The XPD gene product displayed 5-3 helicase activity. The XPD as the XPB protein are also found in the transcription factor TFIIH, a large complex involved in the initiation of transcription The striking discovery that subunits of basal transcription factor TFIIH were involved in Nucleotide Excision Repair (NER) sheds light on a new aspect of NER : a close coupling to transcription via common use of essential factors. TFIIH fulfills a dual role in transcription initiation and NER and the role of TFIIH in NER might closely mimic its role in the transcription initiation process. In transcription initiation TFIIH is thought to be involved in unwinding of the promoter site and to allow promoter clearance. In the NER process TFIIH causes unwinding of the damage containing region that has been localized by XPC-HR23B and XPA-RPA, enabling the accumulation of NER proteins around the damaged site. Contrarely to the XPB helicase, the helicase activity of XPD is indispensable for NER but not for transcription initiation. So, there is much more XPD patients, and only two patients have been described as XP and CS.

Homology

FLYBASE :Xpd ; MGI : Ercc2 (Nb 95413)

Mutations

Germinal

17 mutated sites associated with the xeroderma pigmentosum group D syndrome (among them 3 are also associated with the Cockaynesyndrome) and 15 mutated sites associated with the trichothiodystrophy syndrome

Implicated in

Entity name

xeroderma pigmentosum (XP), XP associated with Cockayne syndrome (CS), and trichothiodystrophy (TTD)

Disease

predisposition to skin cancer: early skin cancers (XPD). Mental and stature abnormalities (XP/CS, and TTD)

Bibliography

Pubmed ID	Last Year	Title	Authors
7697716	1995	Mammalian DNA nucleotide excision repair reconstituted with purified protein components.	Aboussekhra A et al
9192652	1997	Photocarcinogenesis and inhibition of intercellular adhesion molecule 1 expression in cells of DNA-repair-defective individuals.	Ahrens C 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
10667598	2000	The cancer-free phenotype in trichothiodystrophy is unrelated to its repair defect.	Berneburg M et al
9758621	1998	Analysis of mutations in the XPD gene in Italian patients with trichothiodystrophy: site of mutation correlates with repair deficiency, but gene dosage appears to determine clinical severity.	Botta E et al
10644710	2000	Distinct roles for the helicases of TFIIH in transcript initiation and promoter escape.	Bradsher J et al
7920640	1994	Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy.	Broughton BC et al
8590735	1995	Functional retroviral vector for gene therapy of xeroderma pigmentosum group D patients.	Carreau M et al
10949034	2000	Activation of estrogen receptor alpha by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7.	Chen D et al
9025907	1997	Quantitation of ERCC-2 gene expression in human tumor cell lines by reverse transcription-polymerase chain reaction in comparison to northern blot analysis.	Chen ZP et al
9657142	1998	Hair today, gone tomorrow: transgenic mice with human repair deficient hair disease.	Cleaver JE et al
10064601	1999	Mutations in XPB and XPD helicases found in xeroderma pigmentosum patients impair the transcription function of TFIIH.	Coin F et al
9771713	1998	Mutations in the XPD helicase gene result in XP and TTD phenotypes, preventing interaction between XPD and the p44 subunit of TFIIH.	Coin F et al
9278484	1997	Reduced RNA polymerase II transcription in extracts of cockayne syndrome and xeroderma pigmentosum/Cockayne syndrome cells.	Dianov GL et al
8692842	1996	Human cyclin-dependent kinase-activating kinase exists in three distinct complexes.	Drapkin R et al
8152490	1994	Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II.	Drapkin R et al
9771945	1998	Recovery of the normal p53 response after UV treatment in DNA repair-deficient fibroblasts by retroviral-mediated correction with the XPD gene.	Dumaz N et al
9433478	1997	Prolonged p53 protein accumulation in trichothiodystrophy fibroblasts dependent on unrepaired pyrimidine dimers on the transcribed strands of cellular genes.	Dumaz N et al
9351836	1997	Mechanism of open complex and dual incision formation by human nucleotide excision repair factors.	Evans E et al
8824772	1995	Stable SV40-transformation and characterisation of some DNA repair properties of fibroblasts from a trichothiodystrophy patient.	Eveno E et al
1729695	1992	Correction of xeroderma pigmentosum complementation group D mutant cell phenotypes by chromosome and gene transfer: involvement of the human ERCC2 DNA repair gene.	Flejter WL et al
10604009	1999	[Trichothiodystrophy: progresssive manifestations].	Foulc P et al
7849702	1994	Structural and mutational analysis of the xeroderma pigmentosum group D (XPD) gene.	Frederick GD et al
8033104	1994	The human DNA repair gene, ERCC2 (XPD), corrects ultraviolet hypersensitivity and ultraviolet hypermutability of a shuttle vector replicated in xeroderma pigmentosum group D cells.	Gözükara EM et al
8107780	1994	DNA repair gene RAD3 of S. cerevisiae is essential for transcription by RNA polymerase II.	Guzder SN et al
7629061	1995	Lethality in yeast of trichothiodystrophy (TTD) mutations in the human xeroderma pigmentosum group D gene. Implications for transcriptional defect in TTD.	Guzder SN et al
9714461	1998	Expression of DNA excision-repair-cross-complementing proteins p80 and p89 in brain of patients with Down Syndrome and Alzheimer's disease.	Hermon M et al
9101292	1997	Mutations in the XPD gene leading to xeroderma pigmentosum symptoms.	Kobayashi T et al
8612585	1996	Functional interactions between p53 and the TFIIH complex are affected by tumour-associated mutations.	Léveillard T et al
8786141	1996	Sequence analysis of the ERCC2 gene regions in human, mouse, and hamster reveals three linked genes.	Lamerdin JE et al
10786832	2000	Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH, and CSB and implications for Cockayne syndrome.	Le Page F et al
11156600	2001	The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases.	Lehmann AR et al
8392442	1993	UV-induced mutations in a shuttle vector replicated in repair deficient trichothiodystrophy cells differ with those in genetically-related cancer prone xeroderma pigmentosum.	Madzak C et al
1535035	1992	Immune defects in families and patients with xeroderma pigmentosum and trichothiodystrophy.	Mariani E et al
7563073	1995	Characteristics of UV-induced mutation spectra in human XP-D/ERCC2 gene-mutated xeroderma pigmentosum and trichothiodystrophy cells.	Marionnet C et al
8055625	1994	Correction by the ERCC2 gene of UV sensitivity and repair deficiency phenotype in a subset of trichothiodystrophy cells.	Mezzina M et al
7510365	1994	Molecular analysis of the XP-D gene in Italian families with patients affected by trichothiodystrophy and xeroderma pigmentosum group D.	Mondello C et al
10428772	1999	A role for the TFIIH XPB DNA helicase in promoter escape by RNA polymerase II.	Moreland RJ et al
10096550	1999	Differential behaviors toward ultraviolet A and B radiation of fibroblasts and keratinocytes from normal and DNA-repair-deficient patients.	Otto AI et al
8855220	1996	Hepatitis B virus transactivator protein, HBx, associates with the components of TFIIH and stimulates the DNA helicase activity of TFIIH.	Qadri I et al
8960128	1996	Long-term complementation of DNA repair deficient human primary fibroblasts by retroviral transduction of the XPD gene.	Quilliet X et al
8692841	1996	Isolation and characterization of two human transcription factor IIH (TFIIH)-related complexes: ERCC2/CAK and TFIIH.	Reardon JT et al
10604001	1999	[Trichothiodystrophies: anomalies of the repair and transcription of genes].	Robert C et al
9427533	1997	Competent transcription initiation by RNA polymerase II in cell-free extracts from xeroderma pigmentosum groups B and D in an optimized RNA transcription assay.	Satoh MS et al
8194528	1994	The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor.	Schaeffer L et al
11007478	2000	Molecular structure of human TFIIH.	Schultz P et al
7613092	1995	TFIIH: a link between transcription, DNA repair and cell cycle regulation.	Seroz T et al
10924514	2000	p44/SSL1, the regulatory subunit of the XPD/RAD3 helicase, plays a crucial role in the transcriptional activity of TFIIH.	Seroz T et al
1372095	1992	DNA repair investigations in nine Italian patients affected by trichothiodystrophy.	Stefanini M et al
11133811	2000	XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case-control analysis.	Sturgis EM et al
8413672	1993	Human xeroderma pigmentosum group D gene encodes a DNA helicase.	Sung P et al
7585650	1995	Defects in the DNA repair and transcription gene ERCC2 in the cancer-prone disorder xeroderma pigmentosum group D.	Takayama K et al
9238033	1997	Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD (ERCC2) repair/transcription gene.	Taylor EM et al
10024882	1999	Reconstitution of the transcription factor TFIIH: assignment of functions for the three enzymatic subunits, XPB, XPD, and cdk7.	Tirode F et al
9252397	1997	Sequence-specific and domain-specific DNA repair in xeroderma pigmentosum and Cockayne syndrome cells.	Tu Y et al
11062469	2000	Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A trichothiodystrophy disorder.	Vermeulen W et al
11056291	2000	DNA repair capacity: inconsistency between effect of over-expression of five NER genes and the correlation to mRNA levels in primary lymphocytes.	Vogel U et al
8521383	1995	Abrogation of p53-induced apoptosis by the hepatitis B virus X gene.	Wang XW et al
8675009	1996	The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway.	Wang XW et al
7663514	1995	p53 modulation of TFIIH-associated nucleotide excision repair activity.	Wang XW et al
8107888	1994	Transcription factor b (TFIIH) is required during nucleotide-excision repair in yeast.	Wang Z et al
8052270	1994	Molecular analysis of CXPD mutations in the repair-deficient hamster mutants UV5 and UVL-13.	Weber CA et al
2184031	1990	ERCC2: cDNA cloning and molecular characterization of a human nucleotide excision repair gene with high homology to yeast RAD3.	Weber CA et al
9012405	1997	A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy.	Weeda G et al
9771695	1998	From a DNA helicase to brittle hair.	Winkler GS 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
9426063	1998	Disruption of the mouse xeroderma pigmentosum group D DNA repair/basal transcription gene results in preimplantation lethality.	de Boer J et al
9651581	1998	A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy.	de Boer J et al
10416615	1999	Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition.	de Boer J et al
10390531	1999	Cells from XP-D and XP-D-CS patients exhibit equally inefficient repair of UV-induced damage in transcribed genes but different capacity to recover UV-inhibited transcription.	van Hoffen A et al

Other Information

Locus ID:

NCBI: 2068
MIM: 126340
HGNC: 3434
Ensembl: ENSG00000104884

Variants:

dbSNP: 2068
ClinVar: 2068
TCGA: ENSG00000104884
COSMIC: ERCC2

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000104884	ENST00000391941	A8MX75
ENSG00000104884	ENST00000391944	E7EVE9
ENSG00000104884	ENST00000391945	P18074
ENSG00000104884	ENST00000485403	P18074
ENSG00000104884	ENST00000586131	K7EIT8
ENSG00000104884	ENST00000586856	K7ENL1
ENSG00000104884	ENST00000587376	K7EKF3
ENSG00000104884	ENST00000591309	B4E0F6

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
Basal transcription factors	KEGG	ko03022
Nucleotide excision repair	KEGG	ko03420
Basal transcription factors	KEGG	hsa03022
Nucleotide excision repair	KEGG	hsa03420
Holo-TFIIH complex	KEGG	hsa_M00290
Holo-TFIIH complex	KEGG	M00290
Disease	REACTOME	R-HSA-1643685
Infectious disease	REACTOME	R-HSA-5663205
HIV Infection	REACTOME	R-HSA-162906
HIV Life Cycle	REACTOME	R-HSA-162587
Late Phase of HIV Life Cycle	REACTOME	R-HSA-162599
Transcription of the HIV genome	REACTOME	R-HSA-167172
HIV Transcription Initiation	REACTOME	R-HSA-167161
RNA Polymerase II HIV Promoter Escape	REACTOME	R-HSA-167162
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	REACTOME	R-HSA-167160
HIV Transcription Elongation	REACTOME	R-HSA-167169
Formation of the HIV-1 Early Elongation Complex	REACTOME	R-HSA-167158
Tat-mediated elongation of the HIV-1 transcript	REACTOME	R-HSA-167246
Formation of HIV-1 elongation complex containing HIV-1 Tat	REACTOME	R-HSA-167200
Formation of HIV elongation complex in the absence of HIV Tat	REACTOME	R-HSA-167152
Gene Expression	REACTOME	R-HSA-74160
Generic Transcription Pathway	REACTOME	R-HSA-212436
Transcriptional Regulation by TP53	REACTOME	R-HSA-3700989
RNA Polymerase I, RNA Polymerase III, and Mitochondrial Transcription	REACTOME	R-HSA-504046
RNA Polymerase I Transcription	REACTOME	R-HSA-73864
RNA Polymerase I Promoter Clearance	REACTOME	R-HSA-73854
RNA Polymerase I Transcription Initiation	REACTOME	R-HSA-73762
RNA Polymerase I Promoter Escape	REACTOME	R-HSA-73772
RNA Polymerase I Chain Elongation	REACTOME	R-HSA-73777
RNA Polymerase I Transcription Termination	REACTOME	R-HSA-73863
RNA Polymerase II Transcription	REACTOME	R-HSA-73857
RNA Polymerase II Pre-transcription Events	REACTOME	R-HSA-674695
RNA Polymerase II Transcription Pre-Initiation And Promoter Opening	REACTOME	R-HSA-73779
RNA Polymerase II Transcription Initiation And Promoter Clearance	REACTOME	R-HSA-76042
RNA Polymerase II Transcription Initiation	REACTOME	R-HSA-75953
RNA Polymerase II Promoter Escape	REACTOME	R-HSA-73776
RNA Pol II CTD phosphorylation and interaction with CE	REACTOME	R-HSA-77075
RNA Polymerase II Transcription Elongation	REACTOME	R-HSA-75955
Formation of the Early Elongation Complex	REACTOME	R-HSA-113418
Formation of RNA Pol II elongation complex	REACTOME	R-HSA-112382
mRNA Capping	REACTOME	R-HSA-72086
Epigenetic regulation of gene expression	REACTOME	R-HSA-212165
Negative epigenetic regulation of rRNA expression	REACTOME	R-HSA-5250941
NoRC negatively regulates rRNA expression	REACTOME	R-HSA-427413
Metabolism	REACTOME	R-HSA-1430728
Cytosolic iron-sulfur cluster assembly	REACTOME	R-HSA-2564830
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
Gap-filling DNA repair synthesis and ligation in TC-NER	REACTOME	R-HSA-6782210
TP53 Regulates Transcription of DNA Repair Genes	REACTOME	R-HSA-6796648

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PD	PMIDs
PA128406956	fluorouracil	Chemical	ClinicalAnnotation, VariantAnnotation	ambiguous	PD	18267032, 20078613, 20385995, 28796378
PA131285527	oxaliplatin	Chemical	ClinicalAnnotation, VariantAnnotation	associated	PD	18267032, 19434073, 20078613, 20385995, 21449681, 22026922, 22188361, 29662106
PA150595617	platinum	Chemical	ClinicalAnnotation	associated	PD	19434073, 21449681, 22026922, 22188361, 29662106
PA164713176	Platinum compounds	Chemical	ClinicalAnnotation, VariantAnnotation	ambiguous	PD	18347182, 19434073, 21449681, 22026922, 22188361, 23962907, 24446315, 25069034, 25592234, 27498158, 27995989, 28796378, 29662106
PA166122986	radiotherapy	Chemical	VariantAnnotation	not associated	PD	28796378
PA166123026	progression-free survival	Disease	VariantAnnotation	associated	PD
PA166124223	pneumonitis	Disease	ClinicalAnnotation	associated	PD	25069034
PA166151827	adverse events	Disease	ClinicalAnnotation	associated	PD	27498158
PA443314	Alopecia	Disease	ClinicalAnnotation	associated	PD
PA443340	Anemia	Disease	ClinicalAnnotation	associated	PD
PA443560	Breast Neoplasms	Disease	ClinicalAnnotation	associated	PD	25495407
PA443622	Carcinoma, Non-Small-Cell Lung	Disease	ClinicalAnnotation	associated	PD	24446315, 25069034, 27498158
PA444101	Esophageal Neoplasms	Disease	ClinicalAnnotation	associated	PD	19434073, 21449681, 22026922, 22188361, 29662106
PA444773	Leukopenia	Disease	ClinicalAnnotation	associated	PD
PA444937	Mesothelioma	Disease	ClinicalAnnotation	associated	PD
PA445062	Neoplasms	Disease	ClinicalAnnotation	associated	PD	18347182, 22026922, 22188361, 23962907, 24446315, 25592234, 27995989, 29662106
PA445204	Ovarian Neoplasms	Disease	ClinicalAnnotation	associated	PD	19434073, 21449681, 22026922, 22188361, 29662106
PA445218	Pancreatic Neoplasms	Disease	ClinicalAnnotation	associated	PD	19434073, 21449681, 22026922, 22188361, 29662106
PA445601	Osteosarcoma	Disease	ClinicalAnnotation	associated	PD	19434073, 21449681, 22026922, 22188361, 29662106
PA445742	Stomach Neoplasms	Disease	VariantAnnotation	not associated	PD	28796378
PA445828	Testicular Neoplasms	Disease	ClinicalAnnotation	associated	PD
PA446108	Colorectal Neoplasms	Disease	ClinicalAnnotation, VariantAnnotation	associated	PD	18267032, 19434073, 20078613, 20385995, 21449681, 22026922, 22188361, 29662106
PA448645	bleomycin	Chemical	ClinicalAnnotation	associated	PD
PA449014	cisplatin	Chemical	ClinicalAnnotation	associated	PD	19434073, 21449681, 22026922, 22188361, 29662106
PA449383	docetaxel	Chemical	ClinicalAnnotation	associated	PD	25495407
PA449552	etoposide	Chemical	ClinicalAnnotation	associated	PD
PA449748	gemcitabine	Chemical	ClinicalAnnotation	associated	PD
PA450198	leucovorin	Chemical	ClinicalAnnotation, VariantAnnotation	associated	PD	18267032, 20078613, 20385995

References

Pubmed ID	Year	Title	Citations
25096233	2014	Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma.	116
16195237	2006	Polymorphisms of DNA repair genes and risk of non-small cell lung cancer.	112
18509181	2008	Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial.	96
18578568	2008	Crystal structure of the FeS cluster-containing nucleotide excision repair helicase XPD.	96
17466626	2007	Distinct roles for the XPB/p52 and XPD/p44 subcomplexes of TFIIH in damaged DNA opening during nucleotide excision repair.	95
27111033	2016	Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors.	95
11245433	2001	Modulation of nucleotide excision repair capacity by XPD polymorphisms in lung cancer patients.	92
11532866	2001	XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects.	91
16465622	2006	Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes.	91
19913121	2009	Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.	85

Citation

Anne Stary ; Alain Sarasin

ERCC2 (Excision repair cross-complementing rodent repair deficiency, complementation group 2)

Atlas Genet Cytogenet Oncol Haematol. 2001-02-01

Online version: http://atlasgeneticsoncology.org/gene/297/ercc2-(excision-repair-cross-complementing-rodent-repair-deficiency-complementation-group-2)