NEIL1

Nei-like DNA glycosylase 1
PDB rendering based on 1tdh.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1TDH​, 4NRV​
Identifiers
Symbols	NEIL1 ; FPG1; NEI1; hFPG1
External IDs	OMIM: 608844 MGI: 1920024 HomoloGene: 11616 GeneCards: NEIL1 Gene
EC number	4.2.99.18
Gene ontology Molecular function • damaged DNA binding • DNA-(apurinic or apyrimidinic site) lyase activity • protein C-terminus binding • zinc ion binding • hydrolase activity, acting on glycosyl bonds • DNA N-glycosylase activity Cellular component • nucleus • nucleoplasm • chromosome • cytoplasm • microtubule organizing center Biological process • DNA repair • base-excision repair • base-excision repair, AP site formation • nucleotide-excision repair • response to oxidative stress • negative regulation of nuclease activity • depyrimidination Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	79661	72774
Ensembl	ENSG00000140398	ENSMUSG00000032298
UniProt	Q96FI4	Q8K4Q6
RefSeq (mRNA)	NM_001256552	NM_028347
RefSeq (protein)	NP_001243481	NP_082623
Location (UCSC)	Chr 15: 75.35 – 75.36 Mb	Chr 9: 57.14 – 57.15 Mb
PubMed search

Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the NEIL1 gene.^[1][2]

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.^[2]

Targets of NEIL1

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.^[3] 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).^[4] 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,^[5] 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.^[6]

While other DNA repair genes, such as MGMT and MLH1, are often evaluated for epigenetic repression in many types of cancer,^[7] 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.^[8][7] 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.^[9][10] 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.^[11] However, methylation of the promoter region of DNA repair genes (including NEIL1^[6]), are frequently associated with colon cancers and may be an important causal factor for these cancers.^[7]

References

1. 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.
2. "Entrez Gene: NEIL1 nei endonuclease VIII-like 1 (E. coli)".
3. 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.
4. 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.
5. 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. doi:10.1038/srep04186. PMC 3935198. PMID 24569633.
6. 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.
7. Bernstein C, Prasad AR, Nfonsam V, Bernstein H (2013). "DNA Damage, DNA Repair and Cancer". In Chen C. New Research Directions in DNA Repair. InTech. doi:10.5772/53919. ISBN 978-953-51-1114-6.
8. 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.
9. 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.
10. 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.
11. 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. PMID 20420945.

Further reading

• 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, Biological Crystallography 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. 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. doi:10.1038/nature04209. PMID 16189514.
• 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 (48): 175–6. doi:10.1093/nass/48.1.175. PMID 17150535.