NEIL1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNEIL1, FPG1, NEI1, hFPG1, nei like DNA glycosylase 1
External IDsOMIM: 608844 MGI: 1920024 HomoloGene: 11616 GeneCards: NEIL1
Orthologs
SpeciesHumanMouse
Entrez

79661

72774

Ensembl

ENSG00000140398

ENSMUSG00000032298

UniProt

Q96FI4

Q8K4Q6

RefSeq (mRNA)

NM_001256552
NM_024608
NM_001352519
NM_001352520

NM_028347
NM_001357409

RefSeq (protein)

NP_001243481
NP_078884
NP_001339448
NP_001339449

NP_082623
NP_001344338

Location (UCSC)Chr 15: 75.35 – 75.36 MbChr 9: 57.05 – 57.06 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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, 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.

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

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000140398 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032298 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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.
  6. 1 2 "Entrez Gene: NEIL1 nei endonuclease VIII-like 1 (E. coli)".
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. 1 2 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. 1 2 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.

Further reading

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