Defective Base Excision Repair Associated with NEIL1

Stable Identifier
R-HSA-9616334
Type
Pathway
Species
Homo sapiens
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NEIL1 is an enzyme with dual DNA glycosylase and beta/delta lyase activity involved in base excision repair pathway (BER), the primary repair pathway for oxidative DNA damage. NEIL1 can detect and remove DNA damage resulting from oxidation of adenine, guanine and thymine, in the form of 4,6-diamino-5-formamidopyrimidine (FapyA), 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), and thymine glycol (Tg), respectively. NEIL1 can also detect and remove dihydrouracil (DHU), which results from deamination of cytosine. Several low frequency NEIL1 polymorphisms, present in about 1% of general population in the United States have been reported. Different polymorphisms have different effects on NEIL1 function, and it was suggested that NEIL1 polymorphisms and NEIL1 deficiency or haploinsuficiency may be involved in predisposition to cancer and in metabolic syndrome (Roy et al. 2007, Vartanian et al. 2006, Sampath et al. 2011, Prakash et al. 2014). One polymorphism, NEIL1 G83D, is associated with primary sclerosing cholangitis and cholangiocarcinoma (Forsbring et al. 2009). NEIL1 G83D variant exhibits impaired DNA glycosylase activity towards different damaged DNA bases (Roy et al. 2007, Prakash et al. 2014) and induces genomic instability (Galick et al. 2017).
NEIL1 E28del, an in frame deletion variant of NEIL1 reported in gastric (stomach) cancer, where glutamate at position 28 is deleted, does not cleave Tg from damaged DNA (Shinmura et al. 2004).
NEIL1 Q282TER, a NEIL1 variant which lacks the putative nuclear localization signal (NLS), localizes to the cytosol and is therefore not able to access damaged DNA substrates, but its involvement in cancer is uncertain (Shinmura et al. 2015).
Reduced expression of NEIL1 and NEIL2 genes, accompanied with increased NEIL3 gene expression was detected in various cancers. NEIL1 gene silencing by promoter hypermethylation may be one of the underlying mechanisms for reduced NEIL1 expression in cancer (Shinmura et al. 2016).
Infection with the Hepatitis C virus (HCV) leads to decreased NEIL1 expression in liver cells, through an unknown mechanism (Pal et al. 2010).
Mice that are double knockout for Neil1 and Nthl1 genes accumulate DNA damage in the form of FapyA and FapyG and are more prone to development of lung adenocarcinoma than single Neil1 or Nthl1 gene knockouts (Chan et al. 2009). Another study reported that Neil1 knockout mice did not show a predisposition to tumour formation, and neither did double knockouts of Neil1 and Neil2, nor triple knockouts of Neil1, Neil2 and Neil3. Neil1 knockout mice are obese, consistent with the metabolic syndrome, but double knockouts of Neil1 and Neil2 do not display obesity (Rolseth et al. 2017).

Literature References
PubMed ID Title Journal Year
29156764 The NEIL1 G83D germline DNA glycosylase variant induces genomic instability and cellular transformation

Galick, HA, Marsden, CG, Kathe, S, Dragon, JA, Volk, L, Nemec, AA, Wallace, SS, Prakash, A, Doublié, S, Sweasy, JB

Oncotarget 2017
28663564 No cancer predisposition or increased spontaneous mutation frequencies in NEIL DNA glycosylases-deficient mice

Rolseth, V, Luna, L, Olsen, AK, Suganthan, R, Scheffler, K, Neurauter, CG, Esbensen, Y, Kuśnierczyk, A, Hildrestrand, GA, Graupner, A, Andersen, JM, Slupphaug, G, Klungland, A, Nilsen, H, Bjørås, M

Sci Rep 2017
17389588 Human polymorphic variants of the NEIL1 DNA glycosylase

Roy, LM, Jaruga, P, Wood, TG, McCullough, AK, Dizdaroglu, M, Lloyd, RS

J. Biol. Chem. 2007
24382305 Genome and cancer single nucleotide polymorphisms of the human NEIL1 DNA glycosylase: activity, structure, and the effect of editing

Prakash, A, Carroll, BL, Sweasy, JB, Wallace, SS, Doublié, S

DNA Repair (Amst.) 2014
15319300 Inactivating mutations of the human base excision repair gene NEIL1 in gastric cancer

Shinmura, K, Tao, H, Goto, M, Igarashi, H, Taniguchi, T, Maekawa, M, Takezaki, T, Sugimura, H

Carcinogenesis 2004
19346169 Targeted deletion of the genes encoding NTH1 and NEIL1 DNA N-glycosylases reveals the existence of novel carcinogenic oxidative damage to DNA

Chan, MK, Ocampo-Hafalla, MT, Vartanian, V, Jaruga, P, Kirkali, G, Koenig, KL, Brown, S, Lloyd, RS, Dizdaroglu, M, Teebor, GW

DNA Repair (Amst.) 2009
27042257 Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer

Shinmura, K, Kato, H, Kawanishi, Y, Igarashi, H, Goto, M, Tao, H, Inoue, Y, Nakamura, S, Misawa, K, Mineta, H, Sugimura, H

Oxid Med Cell Longev 2016
21285402 Variable penetrance of metabolic phenotypes and development of high-fat diet-induced adiposity in NEIL1-deficient mice

Sampath, H, Batra, AK, Vartanian, V, Carmical, JR, Prusak, D, King, IB, Lowell, B, Earley, LF, Wood, TG, Marks, DL, McCullough, AK, R Stephen, L

Am. J. Physiol. Endocrinol. Metab. 2011
26095805 NEIL1 p.Gln282Stop variant is predominantly localized in the cytoplasm and exhibits reduced activity in suppressing mutations

Shinmura, K, Kato, H, Kawanishi, Y, Goto, M, Tao, H, Inoue, Y, Nakamura, S, Sugimura, H

Gene 2015
19443904 Catalytically impaired hMYH and NEIL1 mutant proteins identified in patients with primary sclerosing cholangitis and cholangiocarcinoma

Forsbring, M, Vik, ES, Dalhus, B, Karlsen, TH, Bergquist, A, Schrumpf, E, Bjørås, M, Boberg, KM, Alseth, I

Carcinogenesis 2009
20074151 Hepatitis C virus induces oxidative stress, DNA damage and modulates the DNA repair enzyme NEIL1

Pal, S, Polyak, SJ, Bano, N, Qiu, WC, Carithers, RL, Shuhart, M, Gretch, DR, Das, A

J. Gastroenterol. Hepatol. 2010
16446448 The metabolic syndrome resulting from a knockout of the NEIL1 DNA glycosylase

Vartanian, V, Lowell, B, Minko, IG, Wood, TG, Ceci, JD, George, S, Ballinger, SW, Corless, CL, McCullough, AK, Lloyd, RS

Proc. Natl. Acad. Sci. U.S.A. 2006
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cancer 162 malignant tumor, malignant neoplasm, primary cancer
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