Defective Base Excision Repair Associated with NTHL1

Stable Identifier
Homo sapiens
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NTHL1 is a DNA N-glycosylase that catalyzes the first step in base excision repair (BER), the primary repair pathway for oxidative DNA damage. NTHL1 can recognize and remove oxidized cytosine, adenine and thymine, in the form of cytosine glycol (Cg), 4,6-diamino-5-formamidopyrimidine (FapyA), and thymine glycol (Tg), respectively. NTHL1 can also recognize and remove dihydrouracil (DHU), produced by cytosine deamination. Germline mutations that impair function of NTHL1 predispose affected patients to a cancer syndrome (NTHL1 syndrome) that involves adenomatous polyposis and colorectal cancer, similar to MUTYH-associated polyposis (MAP), but also causes development of tumors in other organs, such as breast, bladder, skin, uterus and brain. Only patients with mutations in both alleles of NTHL1 are affected, indicative of an autosomally recessive inheritance (Weren et al. 2015, Rivera et al. 2015, Broderick et al. 2017, Grolleman et al. 2019). Some common NTHL1 polymorphisms may results in reduced NTHL1 function, but predisposition of affected individuals to cancer has not been studied in full (Galick et al. 2013). 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). Biallelic loss-of-function mutations in NTHL1 result in a mutational signature characterized by C>T transitions at non-CpG sites (Grolleman et al. 2019). For review, please refer to Weren et al. 2018.
Besides loss-of-function mutations, NTHL1 is amplified and overexpressed in some cancers. NTHL1 overexpression leads to genomic instability in non-transformed human bronchial epithelial cells and may lead to malignant transformation (Limpose et al. 2018).

Literature References
PubMed ID Title Journal Year
23940330 Germ-line variant of human NTH1 DNA glycosylase induces genomic instability and cellular transformation

Galick, HA, Sweasy, JB, Kathe, S, Liu, M, Wallace, SS, Kidane, D, Robey-Bond, S

Proc. Natl. Acad. Sci. U.S.A. 2013
30753826 Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

Sweet, K, Hüneburg, R, Høberg-Vetti, H, Morreau, H, Campbell, IG, Cockburn, D, Kuiper, RA, Ten Broeke, SW, Vink-Börger, ME, Palles, C, Lubinski, J, Sjursen, W, Nielsen, M, de Miranda, NFCC, Schindler, D, Lindsay, H, Lang, A, Hes, FJ, Staninova, M, Elsayed, FA, Clendenning, M, Adlard, J, Li, N, Kamping, EJ, Jongmans, MC, de Voer, RM, Hoogerbrugge, N, Geurts van Kessel, A, Kuiper, RP, van Wezel, T, Ligtenberg, MJL, Aretz, S, Vos, JR, Spasic-Boskovic, O, James, PA, Capellá, G, Valle, L, Grolleman, JE, Ruiz-Ponte, C, Foulkes, WD, Kenwrick, S, Jansen, EAM, Rivera, B, Spier, I, Sijmons, RH, Schackert, HK, Popp, I, Buchanan, DD, Dimovski, AJ, Weren, RDA, Neveling, K, Tomlinson, IP, Dymerska, D

Cancer Cell 2019
29105096 NTHL1 and MUTYH polyposis syndromes: two sides of the same coin?

Kuiper, RP, Geurts van Kessel, A, Hoogerbrugge, N, de Voer, RM, Weren, RD, Ligtenberg, MJ

J. Pathol. 2018
19346169 Targeted deletion of the genes encoding NTH1 and NEIL1 DNA N-glycosylases reveals the existence of novel carcinogenic oxidative damage to DNA

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

DNA Repair (Amst.) 2009
27713038 Validation of Recently Proposed Colorectal Cancer Susceptibility Gene Variants in an Analysis of Families and Patients-a Systematic Review

Broderick, P, Kinnersley, B, Tomlinson, I, Dobbins, SE, Chubb, D, Houlston, RS, Dunlop, MG

Gastroenterology 2017
25938944 A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer

Weren, RD, Kuiper, RP, Ligtenberg, MJ, Geurts van Kessel, A, Hoogerbrugge, N, Verwiel, ET, de Voer, RM, Jongmans, MC, Kamping, EJ, Hoischen, A, van Krieken, JH, Nagtegaal, ID, van Zelst-Stams, WA, Nagengast, FM, Spruijt, L, Tops, BB, Hehir-Kwa, JY, Boyle, EA, Gilissen, C, Shendure, J, Kets, CM

Nat. Genet. 2015
29522130 Overexpression of the base excision repair NTHL1 glycosylase causes genomic instability and early cellular hallmarks of cancer

Ramalingam, SS, Limpose, KL, Corbett, AH, Leung, SW, Werner, EM, Sarker, AH, Trego, KS, Li, Z, Cooper, PK, Shah, JA, Dynan, WS, Doetsch, PW

Nucleic Acids Res. 2018
26559593 Biallelic NTHL1 Mutations in a Woman with Multiple Primary Tumors

Castellsagué, E, Bah, I, van Kempen, LC, Rivera, B, Foulkes, WD

N. Engl. J. Med. 2015
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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