Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the NEIL1gene.[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.
^ abFarkas 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. PMID24811787.
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. PMID12509226.
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. PMID15350146.
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. PMID15533839.
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. PMID16189514. S2CID4427026.
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. PMID16446124.
