Defective Base Excision Repair Associated with NEIL3

Stable Identifier
R-HSA-9629232
Type
Pathway
Species
Homo sapiens
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NEIL3 is a DNA N-glycosylase involved in base excision repair (BER), the primary repair pathway for oxidative DNA damage. NEIL3 can detect and remove oxidized guanine, in the form of 5-guanidinohydatoin and spiroiminodihydantoin, and oxidized thymine, in the form of thymine glycol. NEIL3 has a preference for single strand DNA (ssDNA) and is implicated in repair of oxidative DNA damage at telomeres (Zhou et al. 2013). A NEIL3 disease variant NEIL3 D132 is unable to cleave 5 guanidinohydantoin (Gh) from oxidatively damaged DNA. Individuals harboring a NEIL3 D132V homozygous mutation are predisposed to development of autoimmune diseases (Massaad et al. 2016) and NEIL3 depletion is also associated with an increase in telomere damage and loss (Zhou et al. 2017). NEIL3 unhooks DNA interstrand cross-links (ICLs) during DNA replication. NEIL3 resolves psoralen- and abasic site-induced ICLs in a Fanconi anemia (FA) pathway-independent manner (Semlow et al. 2016, Martin et al. 2017).
A polymorphism in one of the NEIL3 gene splice sites may increase the risk of myocardial infarction (Skarpengland et al. 2015). NEIL3 expression in the heart increases after heart failure in humans and after myocardial infarction in mouse disease models. Neil3 knockout mice show increased mortality after myocardial infarction, but there is no increase in the amount of DNA damage in Neil3 knockout hearts. In the heart, NEIL3 may function in the epigenetic regulation of gene expression and facilitate transcriptional response to myocardial infarction (Olsen et al. 2017). NEIL3 mRNA expression is increased in human carotid plaques and Neil3 deficiency accelerates plaque formation in Apoe knockout mice, but it appears that this is not correlated with oxidative DNA damage (Skarpengland et al. 2016).
The function of NEIL3 in removal of hydantoins from single strand DNA may be important for removal of replication blocks in proliferating cells. Mouse embryonic fibroblasts and neuronal stem cell derived from Neil3 knockout mouse embryos show decreased proliferation capacity and increased sensitivity to DNA damaging agents (Rolseth et al. 2013). NEIL3 may be required for maintenance of adult neurogenesis, as Neil3 knockout mice exhibit learning and memory deficits and synaptic irregularities in the hippocampus (Regnell et al. 2012). In addition, NEIL3 deficient neuronal stem cells exhibits signs of premature senescence (Reis and Hermanson 2012) and Neil3 knockout mice show reduced ability to augment neurogenesis to repair damage induced hypoxia ischemia (Sejersted et al. 2011).
Mice that are triple knockout for Neil1, Neil2 and Neil3 do not show a predisposition to tumour formation or changes in telomere length (Rolseth et al. 2017).

Literature References
PubMed ID Title Journal Year
27693351 Replication-Dependent Unhooking of DNA Interstrand Cross-Links by the NEIL3 Glycosylase

Semlow, DR, Zhang, J, Budzowska, M, Drohat, AC, Walter, JC

Cell 2016
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
22564741 The DNA glycosylases OGG1 and NEIL3 influence differentiation potential, proliferation, and senescence-associated signs in neural stem cells

Reis, A, Hermanson, O

Biochem. Biophys. Res. Commun. 2012
23305905 Loss of Neil3, the major DNA glycosylase activity for removal of hydantoins in single stranded DNA, reduces cellular proliferation and sensitizes cells to genotoxic stress

Rolseth, V, Krokeide, SZ, Kunke, D, Neurauter, CG, Suganthan, R, Sejersted, Y, Hildrestrand, GA, Bjørås, M, Luna, L

Biochim. Biophys. Acta 2013
27328939 Neil3-dependent base excision repair regulates lipid metabolism and prevents atherosclerosis in Apoe-deficient mice

Skarpengland, T, Holm, S, Scheffler, K, Gregersen, I, Dahl, TB, Suganthan, R, Segers, FM, Østlie, I, Otten, JJ, Luna, L, Ketelhuth, DF, Lundberg, AM, Neurauter, CG, Hildrestrand, G, Skjelland, M, Bjørndal, B, Svardal, AM, Iversen, PO, Hedin, U, Nygård, S, Olstad, OK, Krohg-Sørensen, K, Slupphaug, G, Eide, L, Kuśnierczyk, A, Folkersen, L, Ueland, T, Berge, RK, Hansson, GK, Biessen, EA, Halvorsen, B, Bjørås, M, Aukrust, P

Sci Rep 2016
22959434 Hippocampal adult neurogenesis is maintained by Neil3-dependent repair of oxidative DNA lesions in neural progenitor cells

Regnell, CE, Hildrestrand, GA, Sejersted, Y, Medin, T, Moldestad, O, Rolseth, V, Krokeide, SZ, Suganthan, R, Luna, L, Bjørås, M, Bergersen, LH

Cell Rep 2012
23926102 Neil3 and NEIL1 DNA glycosylases remove oxidative damages from quadruplex DNA and exhibit preferences for lesions in the telomeric sequence context

Zhou, J, Liu, M, Fleming, AM, Burrows, CJ, Wallace, SS

J. Biol. Chem. 2013
29234069 The Human DNA glycosylases NEIL1 and NEIL3 Excise Psoralen-Induced DNA-DNA Cross-Links in a Four-Stranded DNA Structure

Martin, PR, Couvé, S, Zutterling, C, Albelazi, MS, Groisman, R, Matkarimov, BT, Parsons, JL, Elder, RH, Saparbaev, MK

Sci Rep 2017
27760045 Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity

Massaad, MJ, Zhou, J, Tsuchimoto, D, Chou, J, Jabara, H, Janssen, E, Glauzy, S, Olson, BG, Morbach, H, Ohsumi, TK, Schmitz, K, Kyriacos, M, Kane, J, Torisu, K, Nakabeppu, Y, Notarangelo, LD, Chouery, E, Megarbane, A, Kang, PB, Al-Idrissi, E, Aldhekri, H, Meffre, E, Mizui, M, Tsokos, GC, Manis, JP, Al-Herz, W, Wallace, SS, Geha, RS

J. Clin. Invest. 2016
25703835 Genetic variants in the DNA repair gene NEIL3 and the risk of myocardial infarction in a nested case-control study. The HUNT Study

Skarpengland, T, Laugsand, LE, Janszky, I, Luna, L, Halvorsen, B, Platou, CG, Wang, W, Vatten, LJ, Damås, JK, Aukrust, P, Bjørås, M, Åsvold, BO

DNA Repair (Amst.) 2015
28854357 NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis

Zhou, J, Chan, J, Lambelé, M, Yusufzai, T, Stumpff, J, Opresko, PL, Thali, M, Wallace, SS

Cell Rep 2017
22065741 Endonuclease VIII-like 3 (Neil3) DNA glycosylase promotes neurogenesis induced by hypoxia-ischemia

Sejersted, Y, Hildrestrand, GA, Kunke, D, Rolseth, V, Krokeide, SZ, Neurauter, CG, Suganthan, R, Atneosen-Åsegg, M, Fleming, AM, Saugstad, OD, Burrows, CJ, Luna, L, Bjørås, M

Proc. Natl. Acad. Sci. U.S.A. 2011
28052262 NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture

Olsen, MB, Hildrestrand, GA, Scheffler, K, Vinge, LE, Alfsnes, K, Palibrk, V, Wang, J, Neurauter, CG, Luna, L, Johansen, J, Øgaard, JDS, Ohm, IK, Slupphaug, G, Kuśnierczyk, A, Fiane, AE, Brorson, SH, Zhang, L, Gullestad, L, Louch, WE, Iversen, PO, Østlie, I, Klungland, A, Christensen, G, Sjaastad, I, Sætrom, P, Yndestad, A, Aukrust, P, Bjørås, M, Finsen, AV

Cell Rep 2017
Participants
Participant Of
Disease
Name Identifier Synonyms
autoimmune hypersensitivity disease 417 autoimmune disease, hypersensitivity reaction type II disease
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