NEIL1 (nei endonuclease VIII-like 1 (E. coli))

2007-07-01   Masaya Suzuki , Kazuya Shinmura , Haruhiko Sugimura 

Department of Pathology, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu, Shizuoka 431-3192, Japan

Identity

HGNC
LOCATION
15q24.2
LOCUSID
ALIAS
FPG1,NEI1,hFPG1
FUSION GENES

DNA/RNA

Description

The NEIL1 gene maps on chromosome 15q24.2 spanning 8,179bp. It contains 11 exons, and the orientation is plus strand.

Transcription

The transcript of 1,828bp, expressed in Brain, Liver, Lung, Kidney, Colon, and Stomach. The NEIL1 gene is up-regulated during S-phase.

Proteins

Atlas Image

Description

NEIL1 encodes 390 amino acids, theoretical molecular weight is 43684 Da, Formamidopyrimidine-DNA glycosylase N-terminal domain and Formamidopyrimidine-DNA glycosylase H2TH domain.

Localisation

Nucleus, centrosome, and mitotic condensed chromosomes.

Function

(1) Bifunctional DNA glycosylase and apurinic/apyrimidinic (AP) lyase that catalyzes beta- and delta-elimination reactions at the site of damaged base.
(2) Reported substrates: thymine glycol (Tg), 5-hydroxycytosine, 5-hydroxyuracil, 5,6-dihydrouracil, 5,6-dihydrothymine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), 4,6-diamino-5-formamidopyrimidine (FapyA), 5-formyluracil, 5-hydroxymethyluracil, spiroiminodihydantoin (Sp), guanidinohydantoin, (Gh) and 8-hydroxyguanine.
(3) Since NEIL1 catalyzes beta- and delta-elimination reactions, the protein generates DNA strand breaks with 3 phosphate termini. In mammalian cells, this 3 phosphate is removed by polynucleotide kinase, but not by . NEIL1 stably interacts with other BER proteins, DNA polymerase beta and DNA ligase III alpha.
(4) In mammalian BER, DNA glycosylases generate abasic (AP) sites, which are then converted to deoxyribo-5-phosphate (dRP) and excised by a dRP lyase (dRPase) activity of DNA polymerase beta. Since NEIL1 also has dRPase activity, NEIL1 has a role as a backup dRPase in mammalian cells.
(5) NEIL1 has a repair activity for oxidized bases in single-strand DNA and bubble DNA, suggesting a possibility that NEIL1 is preferentially involved in repair of lesions in DNA bubbles generated during transcription and/or replication.
(6) Proteins that associate and stimulate the repair activity of NEIL1: a) The (WRN), a member of RecQ family of DNA helicases, b) , , and as individual proteins and as the 9-1-1 complex.
(7) The major DNA glycosylase for the excision of 8-hydroxyguanine is . In the repair of 8-ydroxyguanine by OGG1, after excising the base lesion, OGG1 remains bound to the resulting AP site and does not turn over efficiently. The APE1, which cleaves the phosphodiester bond 5 to the AP site, displaces the bound OGG1 and thus increases its turnover. NEIL1 stimulates turnover of OGG1 in a fashion similar to that of APE1, and carries out beta/delta- elimination at the AP site.
(8) Although OGG1 has limited activity on 8-hydroxyguanine lesion located in the vicinity of the 3 end of a DNA single-strand break, NEIL1 effectively excises the 3 end proximal 8-hydroxyguanine lesion. NEIL1 also effectively excises 5-hydroxyuracil lesions located in the proximity of the 3-end of a DNA single-strand break. (9) The NEIL1 gene is induced by reactive oxygen species.

Homology

Homo sapiens: (NP_659480, 20.1%), (NP_060718, 15.0%) using the CLUSTALW software.

Implicated in

Entity name
Gastric cancer
Note
The following is the abstract of the paper by Shinmura K. et al. (Carcinogenesis, 2004). Oxidized DNA base lesions, such as thymine glycol (Tg) and 8-hydroxyguanine, are often toxic and mutagenic and have been implicated in carcinogenesis. To clarify whether NEIL1 protein, which exhibits excision repair activity towards such base lesions, is involved in gastric carcinogenesis, we examined 71 primary gastric cancers from Japanese patients and four gastric cancer cell lines for mutations and genetic polymorphisms of the NEIL1 gene. We also examined 20 blood samples from Chinese patients for NEIL1 genetic polymorphisms. Three mutations (c.82_84delGAG:p.Glu28del, c.936G > A and c.1000A > G:p.Arg334Gly) and two genetic polymorphisms were identified. When the excision repair activity towards double-stranded oligonucleotide containing a Tg:A base pair was compared among six types of recombinant NEIL1 proteins, p.Glu28del-type NEIL1, found in a primary case, was found to exhibit an extremely low activity level. Moreover, c.936G > A, located in the last nucleotide of exon 10 and detected in the KATO-III cell line, was shown to be associated with a splicing abnormality using an in vivo splicing assay. An immunofluorescence analysis showed that the wild-type NEIL1 protein, but not the truncated protein encoded by the abnormal transcript arising from the c.936G > A mutation, was localized in the nucleus, suggesting that the truncated protein is unlikely to be capable of repairing nuclear DNA. An expression analysis revealed that NEIL1 mRNA expression was reduced in six of 13 (46%) primary gastric cancer specimens that were examined. These results suggest that low NEIL1 activities arising from mutations and reduced expression may be involved in the pathogenesis in a subset of gastric cancers.

Bibliography

Pubmed IDLast YearTitleAuthors
171012342007Different organization of base excision repair of uracil in DNA in nuclei and mitochondria and selective upregulation of mitochondrial uracil-DNA glycosylase after oxidative stress.Akbari M et al
159077752005Action of human endonucleases III and VIII upon DNA-containing tandem dihydrouracil.Ali MM et al
151595822004Overproduction, crystallization and preliminary crystallographic analysis of a novel human DNA-repair enzyme that recognizes oxidative DNA damage.Bandaru V et al
125092262002A novel human DNA glycosylase that removes oxidative DNA damage and is homologous to Escherichia coli endonuclease VIII.Bandaru V et al
176279052007Human endonuclease VIII-like (NEIL) proteins in the giant DNA Mimivirus.Bandaru V et al
176111952007The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1.Das A et al
161182262005Induction of the human oxidized base-specific DNA glycosylase NEIL1 by reactive oxygen species.Das A et al
169789292007Major oxidative products of cytosine are substrates for the nucleotide incision repair pathway.Daviet S et al
145229902003Repair of oxidized bases in DNA bubble structures by human DNA glycosylases NEIL1 and NEIL2.Dou H et al
152320062004The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity.Doublié S et al
169201062006Deoxyribophosphate lyase activity of mammalian endonuclease VIII-like proteins.Grin IR et al
173956412007The human checkpoint sensor Rad9-Rad1-Hus1 interacts with and stimulates NEIL1 glycosylase.Guan X et al
155338362005Recognition of the oxidized lesions spiroiminodihydantoin and guanidinohydantoin in DNA by the mammalian base excision repair glycosylases NEIL1 and NEIL2.Hailer MK et al
119044162002Identification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA.Hazra TK et al
120973172002Identification and characterization of a novel human DNA glycosylase for repair of cytosine-derived lesions.Hazra TK et al
167933612006Purification and characterization of NEIL1 and NEIL2, members of a distinct family of mammalian DNA glycosylases for repair of oxidized bases.Hazra TK et al
175560492007Human NEIL1 localizes with the centrosomes and condensed chromosomes during mitosis.Hildrestrand GA et al
162216812005Repair of formamidopyrimidines in DNA involves different glycosylases: role of the OGG1, NTH1, and NEIL1 enzymes.Hu J et al
150387712004Expression of the oxidative base excision repair enzymes is not induced in TK6 human lymphoblastoid cells after low doses of ionizing radiation.Inoue M et al
155958462004Mouse NEIL1 protein is specific for excision of 2,6-diamino-4-hydroxy-5-formamidopyrimidine and 4,6-diamino-5-formamidopyrimidine from oxidatively damaged DNA.Jaruga P et al
174328292007Lesion specificity in the base excision repair enzyme hNeil1: modeling and dynamics studies.Jia L et al
147345542004Differential specificity of human and Escherichia coli endonuclease III and VIII homologues for oxidative base lesions.Katafuchi A et al
126002122003Cross-linking of 2-deoxyribonolactone and its beta-elimination product by base excision repair enzymes.Kroeger KM et al
147264822004Stereoselective excision of thymine glycol from oxidatively damaged DNA.Miller H et al
153501462004Stimulation of DNA glycosylase activity of OGG1 by NEIL1: functional collaboration between two human DNA glycosylases.Mokkapati SK et al
124339962002Human DNA glycosylases of the bacterial Fpg/MutM superfamily: an alternative pathway for the repair of 8-oxoguanine and other oxidation products in DNA.Morland I et al
164461242006Repair of thymine glycol by hNth1 and hNeil1 is modulated by base pairing and cis-trans epimerization.Ocampo-Hafalla MT et al
173486892007NEIL1 is the major DNA glycosylase that processes 5-hydroxyuracil in the proximity of a DNA single-strand break.Parsons JL et al
127138152003The novel DNA glycosylase, NEIL1, protects mammalian cells from radiation-mediated cell death.Rosenquist TA et al
173895882007Human polymorphic variants of the NEIL1 DNA glycosylase.Roy LM et al
165451102006Association between cigarette smoking, APC mutations and the risk of developing sporadic colorectal adenomas and carcinomas.Sarebø M et al
153193002004Inactivating mutations of the human base excision repair gene NEIL1 in gastric cancer.Shinmura K et al
122004412002A back-up glycosylase in Nth1 knock-out mice is a functional Nei (endonuclease VIII) homologue.Takao M et al
164464482006The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase.Vartanian V et al
152609722004AP endonuclease-independent DNA base excision repair in human cells.Wiederhold L et al
155338392005DNA glycosylase activities for thymine residues oxidized in the methyl group are functions of the hNEIL1 and hNTH1 enzymes in human cells.Zhang QM et al

Other Information

Locus ID:

NCBI: 79661
MIM: 608844
HGNC: 18448
Ensembl: ENSG00000140398

Variants:

dbSNP: 79661
ClinVar: 79661
TCGA: ENSG00000140398
COSMIC: NEIL1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000140398ENST00000355059Q96FI4
ENSG00000140398ENST00000564257H3BST2
ENSG00000140398ENST00000564500H3BRZ2
ENSG00000140398ENST00000564784Q96FI4
ENSG00000140398ENST00000565051H3BT75
ENSG00000140398ENST00000566313H3BT94
ENSG00000140398ENST00000566752H3BU98
ENSG00000140398ENST00000567005H3BM98
ENSG00000140398ENST00000567657H3BQU8
ENSG00000140398ENST00000568059H3BQE8
ENSG00000140398ENST00000568519H3BSZ5
ENSG00000140398ENST00000568881H3BN83
ENSG00000140398ENST00000569035Q96FI4
ENSG00000140398ENST00000569506H3BTX5

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Base excision repairKEGGko03410
Base excision repairKEGGhsa03410
DNA RepairREACTOMER-HSA-73894
Base Excision RepairREACTOMER-HSA-73884
Base-Excision Repair, AP Site FormationREACTOMER-HSA-73929
DepyrimidinationREACTOMER-HSA-73928
Recognition and association of DNA glycosylase with site containing an affected pyrimidineREACTOMER-HSA-110328
Cleavage of the damaged pyrimidineREACTOMER-HSA-110329
Resolution of Abasic Sites (AP sites)REACTOMER-HSA-73933
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement PathwayREACTOMER-HSA-5649702

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA128406956fluorouracilChemicalVariantAnnotationnot associatedPD28796378
PA164713176Platinum compoundsChemicalVariantAnnotationnot associatedPD28796378
PA166122986radiotherapyChemicalVariantAnnotationnot associatedPD28796378
PA445742Stomach NeoplasmsDiseaseVariantAnnotationnot associatedPD28796378

References

Pubmed IDYearTitleCitations
145229902003Repair of oxidized bases in DNA bubble structures by human DNA glycosylases NEIL1 and NEIL2.144
125092262002A novel human DNA glycosylase that removes oxidative DNA damage and is homologous to Escherichia coli endonuclease VIII.135
190471282008Single nucleotide polymorphisms of microRNA machinery genes modify the risk of renal cell carcinoma.99
124339962002Human DNA glycosylases of the bacterial Fpg/MutM superfamily: an alternative pathway for the repair of 8-oxoguanine and other oxidation products in DNA.95
185439452008Superior removal of hydantoin lesions relative to other oxidized bases by the human DNA glycosylase hNEIL1.80
180323762008Interaction of the human DNA glycosylase NEIL1 with proliferating cell nuclear antigen. The potential for replication-associated repair of oxidized bases in mammalian genomes.75
152320062004The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity.62
210683682010RNA editing changes the lesion specificity for the DNA repair enzyme NEIL1.59
176111952007The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1.54
147345542004Differential specificity of human and Escherichia coli endonuclease III and VIII homologues for oxidative base lesions.52

Citation

Masaya Suzuki ; Kazuya Shinmura ; Haruhiko Sugimura

NEIL1 (nei endonuclease VIII-like 1 (E. coli))

Atlas Genet Cytogenet Oncol Haematol. 2007-07-01

Online version: http://atlasgeneticsoncology.org/gene/41519/neil1