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NEIL1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1TDH, 4NRV, 5ITY, 5ITQ, 5ITU, 5ITX, 5ITR, 5ITT
Identifiers
Aliases	NEIL1, FPG1, NEI1, hFPG1, nei like DNA glycosylase 1
External IDs	OMIM: 608844; MGI: 1920024; HomoloGene: 11616; GeneCards: NEIL1; OMA:NEIL1 - orthologs
Gene location (Human)
Chr.	Chromosome 15 (human)
End	75,357,115 bp
Gene location (Mouse)
Chr.	Chromosome 9 (mouse)
End	57,055,589 bp
RNA expression pattern
	Top expressed in
	right uterine tube; ; right hemisphere of cerebellum; ; right adrenal cortex; ; right frontal lobe; ; minor salivary glands; ; left adrenal cortex; ; canal of the cervix; ; right lobe of liver; ; right lobe of thyroid gland; ; anterior pituitary;
	Top expressed in
	mesenteric lymph nodes; ; thymus; ; submandibular gland; ; otolith organ; ; utricle; ; brown adipose tissue; ; hand; ; right kidney; ; proximal tubule; ; muscle of thigh;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	DNA binding; zinc ion binding; hydrolase activity, hydrolyzing N-glycosyl compounds; hydrolase activity, acting on glycosyl bonds; damaged DNA binding; protein C-terminus binding; catalytic activity; lyase activity; nucleic acid binding; hydrolase activity; DNA N-glycosylase activity; DNA-(apurinic or apyrimidinic site) endonuclease activity; class I DNA-(apurinic or apyrimidinic site) endonuclease activity;
Cellular component	cytoplasm; chromosome; microtubule organizing center; cytoskeleton; nucleus; nucleoplasm;
Biological process	nucleotide-excision repair; response to oxidative stress; cellular response to DNA damage stimulus; depyrimidination; negative regulation of nuclease activity; metabolism; DNA repair; base-excision repair;
	Sources:Amigo / QuickGO
Orthologs
	79661
	72774
	ENSG00000140398
	ENSMUSG00000032298
	Q96FI4
	Q8K4Q6
	NM_001256552; NM_024608; NM_001352519; NM_001352520
	NM_028347; NM_001357409
	NP_001243481; NP_078884; NP_001339448; NP_001339449
	NP_082623; NP_001344338
	Wikidata
View/Edit Human	View/Edit Mouse

Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the NEIL1 gene.^[5]^[6]

NEIL1 belongs to a class of DNA glycosylases homologous to the bacterial Fpg/Nei family. These glycosylases initiate the first step in base excision repair by cleaving bases damaged by reactive oxygen species (ROS) and introducing a DNA strand break via the associated lyase reaction.^[6]

Targets

NEIL1 recognizes (targets) and removes certain ROS-damaged bases and then incises the abasic site via β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized pyrimidines, formamidopyrimidines, thymine residues oxidized at the methyl group, and both stereoisomers of thymine glycol.^[7] The best substrates for human NEIL1 appear to be the hydantoin lesions, guanidinohydantoin, and spiroiminodihydantoin that are further oxidation products of 8-oxoG. NEIL1 is also capable of removing lesions from single-stranded DNA as well as from bubble and forked DNA structures. Because the expression of NEIL1 is cell-cycle dependent, and because it acts on forked DNA structures and interacts with PCNA and FEN-1, it has been proposed that NEIL1 functions in replication associated DNA repair.

Deficiency in cancer

NEIL1 is one of the DNA repair genes most frequently hypermethylated in head and neck squamous cell carcinoma (HNSCC).^[8] When 160 human DNA repair genes were evaluated for aberrant methylation in HNSCC tumors, 62% of tumors were hypermethylated in the NEIL1 promoter region, causing NEIL1 messenger RNA and NEIL1 protein to be repressed. When 8 DNA repair genes were evaluated in non-small cell lung cancer (NSCLC) tumors,^[9] 42% were hypermethylated in the NEIL1 promoter region. This was the most frequent DNA repair deficiency found among the 8 DNA repair genes tested. NEIL1 was also one of six DNA repair genes found to be hypermethylated in their promoter regions in colorectal cancer.^[10]

While other DNA repair genes, such as MGMT and MLH1, are often evaluated for epigenetic repression in many types of cancer,^{[citation needed]} epigenetic deficiency of NEIL1 is usually not evaluated, but might be of importance in such cancers as well.

DNA damage appears to be the primary underlying cause of cancer.^[11] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutational errors during DNA replication due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair.^[12]^[13] Such mutations and epigenetic alterations may give rise to cancer (see malignant neoplasms).

In colon cancer, germ line mutations in DNA repair genes cause only 2–5% of cases.^[14] However, methylation of the promoter region of DNA repair genes (including NEIL1^[10]), are frequently associated with colon cancers and may be an important causal factor for these cancers.^{[citation needed]}

Memory retention

NEIL1 promotes short-term spatial memory retention. Mice lacking NEIL1 have impaired memory retention in a water maze test.^[15]

Stroke prevention

NEIL1 also protects against ischemic stroke-induced brain dysfunction and death in mice.^[15] NEIL1 deficiency causes brain damage and a functionally defective outcome in a mouse model of stroke.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000140398 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000032298 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Hazra TK, Izumi T, Boldogh I, Imhoff B, Kow YW, Jaruga P, Dizdaroglu M, Mitra S (Mar 2002). "Identification and characterization of a human DNA glycosylase for repair of modified bases in oxidatively damaged DNA". Proceedings of the National Academy of Sciences of the United States of America. 99 (6): 3523–8. doi:10.1073/pnas.062053799. PMC 122556. PMID 11904416.
^ ^a ^b "Entrez Gene: NEIL1 nei endonuclease VIII-like 1 (E. coli)".
^ Nemec AA, Wallace SS, Sweasy JB (Oct 2010). "Variant base excision repair proteins: contributors to genomic instability". Seminars in Cancer Biology. 20 (5): 320–8. doi:10.1016/j.semcancer.2010.10.010. PMC 3254599. PMID 20955798.
^ Chaisaingmongkol J, Popanda O, Warta R, Dyckhoff G, Herpel E, Geiselhart L, Claus R, Lasitschka F, Campos B, Oakes CC, Bermejo JL, Herold-Mende C, Plass C, Schmezer P (Dec 2012). "Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma". Oncogene. 31 (49): 5108–16. doi:10.1038/onc.2011.660. PMID 22286769.
^ Do H, Wong NC, Murone C, John T, Solomon B, Mitchell PL, Dobrovic A (2014). "A critical re-assessment of DNA repair gene promoter methylation in non-small cell lung carcinoma". Scientific Reports. 4: 4186. Bibcode:2014NatSR...4E4186D. doi:10.1038/srep04186. PMC 3935198. PMID 24569633.
^ ^a ^b Farkas SA, Vymetalkova V, Vodickova L, Vodicka P, Nilsson TK (Apr 2014). "DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/β-catenin signaling pathway genes". Epigenomics. 6 (2): 179–91. doi:10.2217/epi.14.7. PMID 24811787.
^ Kastan MB (2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Mol. Cancer Res. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632.
^ O'Hagan HM, Mohammad HP, Baylin SB (2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLOS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159.
^ Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV (Jul 2007). "DNA damage, homology-directed repair, and DNA methylation". PLOS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978.
^ Jasperson KW, Tuohy TM, Neklason DW, Burt RW (Jun 2010). "Hereditary and familial colon cancer". Gastroenterology. 138 (6): 2044–58. doi:10.1053/j.gastro.2010.01.054. PMC 3057468. PMID 20420945.
^ ^a ^b Canugovi C, Yoon JS, Feldman NH, Croteau DL, Mattson MP, Bohr VA (September 2012). "Endonuclease VIII-like 1 (NEIL1) promotes short-term spatial memory retention and protects from ischemic stroke-induced brain dysfunction and death in mice". Proc. Natl. Acad. Sci. U.S.A. 109 (37): 14948–53. Bibcode:2012PNAS..10914948C. doi:10.1073/pnas.1204156109. PMC 3443144. PMID 22927410.

Takao M, Kanno S, Kobayashi K, Zhang QM, Yonei S, van der Horst GT, Yasui A (Nov 2002). "A back-up glycosylase in Nth1 knock-out mice is a functional Nei (endonuclease VIII) homologue". The Journal of Biological Chemistry. 277 (44): 42205–13. doi:10.1074/jbc.M206884200. PMID 12200441.
Morland I, Rolseth V, Luna L, Rognes T, Bjørås M, Seeberg E (Nov 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". Nucleic Acids Research. 30 (22): 4926–36. doi:10.1093/nar/gkf618. PMC 137166. PMID 12433996.
Bandaru V, Sunkara S, Wallace SS, Bond JP (Jul 2002). "A novel human DNA glycosylase that removes oxidative DNA damage and is homologous to Escherichia coli endonuclease VIII". DNA Repair. 1 (7): 517–29. doi:10.1016/S1568-7864(02)00036-8. PMID 12509226.
Dou H, Mitra S, Hazra TK (Dec 2003). "Repair of oxidized bases in DNA bubble structures by human DNA glycosylases NEIL1 and NEIL2". The Journal of Biological Chemistry. 278 (50): 49679–84. doi:10.1074/jbc.M308658200. PMID 14522990.
Katafuchi A, Nakano T, Masaoka A, Terato H, Iwai S, Hanaoka F, Ide H (Apr 2004). "Differential specificity of human and Escherichia coli endonuclease III and VIII homologues for oxidative base lesions". The Journal of Biological Chemistry. 279 (14): 14464–71. doi:10.1074/jbc.M400393200. PMID 14734554.
Bandaru V, Cooper W, Wallace SS, Doublié S (Jun 2004). "Overproduction, crystallization and preliminary crystallographic analysis of a novel human DNA-repair enzyme that recognizes oxidative DNA damage". Acta Crystallographica Section D. 60 (Pt 6): 1142–4. doi:10.1107/S0907444904007929. PMID 15159582.
Doublié S, Bandaru V, Bond JP, Wallace SS (Jul 2004). "The crystal structure of human endonuclease VIII-like 1 (NEIL1) reveals a zincless finger motif required for glycosylase activity". Proceedings of the National Academy of Sciences of the United States of America. 101 (28): 10284–9. Bibcode:2004PNAS..10110284D. doi:10.1073/pnas.0402051101. PMC 478564. PMID 15232006.
Wiederhold L, Leppard JB, Kedar P, Karimi-Busheri F, Rasouli-Nia A, Weinfeld M, Tomkinson AE, Izumi T, Prasad R, Wilson SH, Mitra S, Hazra TK (Jul 2004). "AP endonuclease-independent DNA base excision repair in human cells". Molecular Cell. 15 (2): 209–20. doi:10.1016/j.molcel.2004.06.003. PMID 15260972.
Shinmura K, Tao H, Goto M, Igarashi H, Taniguchi T, Maekawa M, Takezaki T, Sugimura H (Dec 2004). "Inactivating mutations of the human base excision repair gene NEIL1 in gastric cancer". Carcinogenesis. 25 (12): 2311–7. doi:10.1093/carcin/bgh267. PMID 15319300.
Mokkapati SK, Wiederhold L, Hazra TK, Mitra S (Sep 2004). "Stimulation of DNA glycosylase activity of OGG1 by NEIL1: functional collaboration between two human DNA glycosylases". Biochemistry. 43 (36): 11596–604. doi:10.1021/bi049097i. PMID 15350146.
Zhang QM, Yonekura S, Takao M, Yasui A, Sugiyama H, Yonei S (Jan 2005). "DNA glycosylase activities for thymine residues oxidized in the methyl group are functions of the hNEIL1 and hNTH1 enzymes in human cells". DNA Repair. 4 (1): 71–9. doi:10.1016/j.dnarep.2004.08.002. PMID 15533839.
Das A, Hazra TK, Boldogh I, Mitra S, Bhakat KK (Oct 2005). "Induction of the human oxidized base-specific DNA glycosylase NEIL1 by reactive oxygen species". The Journal of Biological Chemistry. 280 (42): 35272–80. doi:10.1074/jbc.M505526200. PMID 16118226.
Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
Ocampo-Hafalla MT, Altamirano A, Basu AK, Chan MK, Ocampo JE, Cummings A, Boorstein RJ, Cunningham RP, Teebor GW (Apr 2006). "Repair of thymine glycol by hNth1 and hNeil1 is modulated by base pairing and cis-trans epimerization". DNA Repair. 5 (4): 444–54. doi:10.1016/j.dnarep.2005.12.004. PMID 16446124.
Broderick P, Bagratuni T, Vijayakrishnan J, Lubbe S, Chandler I, Houlston RS (2006). "Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition". BMC Cancer. 6: 243. doi:10.1186/1471-2407-6-243. PMC 1624846. PMID 17029639.
Katafuchi A, Matsubara M, Terato H, Iwai S, Hanaoka F, Ide H (2007). "Damage specificity of human DNA glycosylases for oxidative pyrimidine lesions". Nucleic Acids Symposium Series. 48 (1): 175–6. doi:10.1093/nass/48.1.175. PMID 17150535.