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

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

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

Identity

HGNC

NEIL1

LOCATION

15q24.2

LOCUSID

79661

ALIAS

FPG1,NEI1,hFPG1

FUSION GENES

Show Gene Fusions

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

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 ID	Last Year	Title	Authors
17101234	2007	Different 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
15907775	2005	Action of human endonucleases III and VIII upon DNA-containing tandem dihydrouracil.	Ali MM et al
15159582	2004	Overproduction, crystallization and preliminary crystallographic analysis of a novel human DNA-repair enzyme that recognizes oxidative DNA damage.	Bandaru V et al
12509226	2002	A novel human DNA glycosylase that removes oxidative DNA damage and is homologous to Escherichia coli endonuclease VIII.	Bandaru V et al
17627905	2007	Human endonuclease VIII-like (NEIL) proteins in the giant DNA Mimivirus.	Bandaru V et al
17611195	2007	The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1.	Das A et al
16118226	2005	Induction of the human oxidized base-specific DNA glycosylase NEIL1 by reactive oxygen species.	Das A et al
16978929	2007	Major oxidative products of cytosine are substrates for the nucleotide incision repair pathway.	Daviet S et al
14522990	2003	Repair of oxidized bases in DNA bubble structures by human DNA glycosylases NEIL1 and NEIL2.	Dou H et al
15232006	2004	The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity.	Doublié S et al
16920106	2006	Deoxyribophosphate lyase activity of mammalian endonuclease VIII-like proteins.	Grin IR et al
17395641	2007	The human checkpoint sensor Rad9-Rad1-Hus1 interacts with and stimulates NEIL1 glycosylase.	Guan X et al
15533836	2005	Recognition of the oxidized lesions spiroiminodihydantoin and guanidinohydantoin in DNA by the mammalian base excision repair glycosylases NEIL1 and NEIL2.	Hailer MK et al
11904416	2002	Identification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA.	Hazra TK et al
12097317	2002	Identification and characterization of a novel human DNA glycosylase for repair of cytosine-derived lesions.	Hazra TK et al
16793361	2006	Purification and characterization of NEIL1 and NEIL2, members of a distinct family of mammalian DNA glycosylases for repair of oxidized bases.	Hazra TK et al
17556049	2007	Human NEIL1 localizes with the centrosomes and condensed chromosomes during mitosis.	Hildrestrand GA et al
16221681	2005	Repair of formamidopyrimidines in DNA involves different glycosylases: role of the OGG1, NTH1, and NEIL1 enzymes.	Hu J et al
15038771	2004	Expression 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
15595846	2004	Mouse 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
17432829	2007	Lesion specificity in the base excision repair enzyme hNeil1: modeling and dynamics studies.	Jia L et al
14734554	2004	Differential specificity of human and Escherichia coli endonuclease III and VIII homologues for oxidative base lesions.	Katafuchi A et al
12600212	2003	Cross-linking of 2-deoxyribonolactone and its beta-elimination product by base excision repair enzymes.	Kroeger KM et al
14726482	2004	Stereoselective excision of thymine glycol from oxidatively damaged DNA.	Miller H et al
15350146	2004	Stimulation of DNA glycosylase activity of OGG1 by NEIL1: functional collaboration between two human DNA glycosylases.	Mokkapati SK et al
12433996	2002	Human 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
16446124	2006	Repair of thymine glycol by hNth1 and hNeil1 is modulated by base pairing and cis-trans epimerization.	Ocampo-Hafalla MT et al
17348689	2007	NEIL1 is the major DNA glycosylase that processes 5-hydroxyuracil in the proximity of a DNA single-strand break.	Parsons JL et al
12713815	2003	The novel DNA glycosylase, NEIL1, protects mammalian cells from radiation-mediated cell death.	Rosenquist TA et al
17389588	2007	Human polymorphic variants of the NEIL1 DNA glycosylase.	Roy LM et al
16545110	2006	Association between cigarette smoking, APC mutations and the risk of developing sporadic colorectal adenomas and carcinomas.	Sarebø M et al
15319300	2004	Inactivating mutations of the human base excision repair gene NEIL1 in gastric cancer.	Shinmura K et al
12200441	2002	A back-up glycosylase in Nth1 knock-out mice is a functional Nei (endonuclease VIII) homologue.	Takao M et al
16446448	2006	The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase.	Vartanian V et al
15260972	2004	AP endonuclease-independent DNA base excision repair in human cells.	Wiederhold L et al
15533839	2005	DNA 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 ID	Transcript ID	Uniprot
ENSG00000140398	ENST00000355059	Q96FI4
ENSG00000140398	ENST00000564257	H3BST2
ENSG00000140398	ENST00000564500	H3BRZ2
ENSG00000140398	ENST00000564784	Q96FI4
ENSG00000140398	ENST00000565051	H3BT75
ENSG00000140398	ENST00000566313	H3BT94
ENSG00000140398	ENST00000566752	H3BU98
ENSG00000140398	ENST00000567005	H3BM98
ENSG00000140398	ENST00000567657	H3BQU8
ENSG00000140398	ENST00000568059	H3BQE8
ENSG00000140398	ENST00000568519	H3BSZ5
ENSG00000140398	ENST00000568881	H3BN83
ENSG00000140398	ENST00000569035	Q96FI4
ENSG00000140398	ENST00000569506	H3BTX5

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
Base excision repair	KEGG	ko03410
Base excision repair	KEGG	hsa03410
DNA Repair	REACTOME	R-HSA-73894
Base Excision Repair	REACTOME	R-HSA-73884
Base-Excision Repair, AP Site Formation	REACTOME	R-HSA-73929
Depyrimidination	REACTOME	R-HSA-73928
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	REACTOME	R-HSA-110328
Cleavage of the damaged pyrimidine	REACTOME	R-HSA-110329
Resolution of Abasic Sites (AP sites)	REACTOME	R-HSA-73933
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	REACTOME	R-HSA-5649702

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PD	PMIDs
PA128406956	fluorouracil	Chemical	VariantAnnotation	not associated	PD	28796378
PA164713176	Platinum compounds	Chemical	VariantAnnotation	not associated	PD	28796378
PA166122986	radiotherapy	Chemical	VariantAnnotation	not associated	PD	28796378
PA445742	Stomach Neoplasms	Disease	VariantAnnotation	not associated	PD	28796378

References

Pubmed ID	Year	Title	Citations
38795603	2024	Functional characterization of single nucleotide polymorphic variants of DNA repair enzyme NEIL1 in South Asian populations.	0
38795603	2024	Functional characterization of single nucleotide polymorphic variants of DNA repair enzyme NEIL1 in South Asian populations.	0
37517321	2023	Functional analyses of single nucleotide polymorphic variants of the DNA glycosylase NEIL1 in sub-Saharan African populations.	2
37517321	2023	Functional analyses of single nucleotide polymorphic variants of the DNA glycosylase NEIL1 in sub-Saharan African populations.	2
35190641	2022	p53-NEIL1 co-abnormalities induce genomic instability and promote synthetic lethality with Chk1 inhibition in multiple myeloma having concomitant 17p13(del) and 1q21(gain).	4
35917336	2022	NEIL1 Recoding due to RNA Editing Impacts Lesion-Specific Recognition and Excision.	4
35190641	2022	p53-NEIL1 co-abnormalities induce genomic instability and promote synthetic lethality with Chk1 inhibition in multiple myeloma having concomitant 17p13(del) and 1q21(gain).	4
35917336	2022	NEIL1 Recoding due to RNA Editing Impacts Lesion-Specific Recognition and Excision.	4
33300026	2021	Heritable pattern of oxidized DNA base repair coincides with pre-targeting of repair complexes to open chromatin.	18
33498912	2021	Effect of DNA Glycosylases OGG1 and Neil1 on Oxidized G-Rich Motif in the KRAS Promoter.	4
33595290	2021	DNA Sequence Modulates the Efficiency of NEIL1-Catalyzed Excision of the Aflatoxin B(1)-Induced Formamidopyrimidine Guanine Adduct.	8
33925271	2021	NEIL1 and NEIL2 Are Recruited as Potential Backup for OGG1 upon OGG1 Depletion or Inhibition by TH5487.	6
33929180	2021	RNA Editing of the Human DNA Glycosylase NEIL1 Alters Its Removal of 5-Hydroxyuracil Lesions in DNA.	3
34105905	2021	Genetic variations in DNA repair gene NEIL1 associated with radiation pneumonitis risk in lung cancer patients.	1
34226550	2021	DNA repair glycosylase hNEIL1 triages damaged bases via competing interaction modes.	5

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