Defective OGG1 mutants do not excise 8-oxoguanine

Stable Identifier
R-HSA-9656250
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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OGG1 missense mutants OGG1 R46Q (Audebert, Chevillard et al. 2000; Audebert, Radicella et al. 2000), reported in clear cell renal carcinoma, and OGG1 R154H (Audebert, Radicella et al. 2000), reported in gastric cancer cell line MKN4 (Bruner et al. 2000), show a diminished 8-oxoguanine (8oxoG)-directed DNA glycosylase activity, with the function of OGG1 R154H being more severely impaired. The first functional study of OGG1 R154H reported catalytic activity similar to the wild type OGG1, but promiscuous substrate binding, which could result in a mutator phenotype (Bruner et al. 2000).
OGG1 R131Q mutant, reported in lung cancer, shows the loss of 8oxoG-directed glycolytic activity (Chevillard et al. 1998), which, based on structural studies, is predicted to be the consequence of misfolding of the active site (Bruner et al. 2000, Anderson and Dagget 2009). Distortion of the active site was also found to be the cause of impaired function of OGG1 R46Q and OGG1 R154H.
OGG1 missense mutant, OGG1 R229Q, reported in the acute myeloid leukemia-derived cell line KG-1, shows a loss of 8oxoG-directed DNA glycosylase activity (Hyun et al. 2000, Hyun et al. 2002), which is due to thermolability of the OGG1 R229Q mutant (Hill and Evans 2007).
OGG1 frameshift mutant, OGG1 P266fs139*, reported in Alzheimer's disease, exhibits loss of glycosylase activity and is unable to excise 8oxoG from damaged DNA (Mao et al. 2007).
It is uncertain whether substrate binding is affected in OGG1 R46Q, OGG1 R229Q and OGG1 P266fs139*. Excision of FapyG from dsDNA by OGG1 R46Q, OGG1 R131Q, OGG1 R229Q and OGG1 P266fs139* has not been tested.
OGG1 R46L and OGG1 R131G have not been functionally studied but have been reported in cancer and predicted to be pathogenic. They are annotated as candidate disease variants based on their similarity with OGG1 R46Q and OGG1 R131Q, respectively.
OGG1 S326C is a frequent genetic polymorphism in people of European and Asian descent. OGG1 S326C variant is susceptible to oxidation, leading to diminished catalytic activity and accumulation of 8oxoG (Yamane et al. 2004, Moritz et al. 2014) under conditions of oxidative stress (Kershaw and Hodges 2012). This may be due to decreased specificity of OGG1 S326C for 8oxoG (Dherin et al. 1999).
Lysine 249 (K249) of OGG1 is directly involved in the nucleophilic attack of the N-glycosidic bond while aspartate 268 (D268) of OGG1 primes K249 for the nucleophilic attack. Both K249 and D268 are critical for the excision of 8oxoG lesions from damaged DNA. By directed mutagenesis, OGG1 K249Q (Nash et al. 1997), OGG1 D268A (Bjoras et al. 2002) and OGG1 D268N (Bjoras et al. 2002, Norman et al. 2003, Sebera et al. 2017) mutants were shown to be non-functional in 8oxoG cleavage. Naturally occurring variant alleles of OGG1 that produce OGG1 K249Q, OGG1 D268A and OGG1 D268N have been reported in human populations (ClinGene Allele Registry - Pawliczek et al. 2018) but have so far not been associated with a specific disease.

Literature References
PubMed ID Title Journal Year
10908322 Effect of single mutations in the OGG1 gene found in human tumors on the substrate specificity of the Ogg1 protein

Audebert, M, Radicella, JP, Dizdaroglu, M

Nucleic Acids Res. 2000
11902834 Reciprocal "flipping" underlies substrate recognition and catalytic activation by the human 8-oxo-guanine DNA glycosylase

Bjørås, M, Seeberg, E, Luna, L, Pearl, LH, Barrett, TE

J. Mol. Biol. 2002
17651912 A novel R229Q OGG1 polymorphism results in a thermolabile enzyme that sensitizes KG-1 leukemia cells to DNA damaging agents

Hill, JW, Evans, MK

Cancer Detect. Prev. 2007
9662341 Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours

Chevillard, S, Radicella, JP, Levalois, C, Lebeau, J, Poupon, MF, Oudard, S, Dutrillaux, B, Boiteux, S

Oncogene 1998
12578369 Structural and biochemical exploration of a critical amino acid in human 8-oxoguanine glycosylase

Norman, DP, Chung, SJ, Verdine, GL

Biochemistry 2003
10706276 Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA

Bruner, SD, Norman, DP, Verdine, GL

Nature 2000
28334993 The mechanism of the glycosylase reaction with hOGG1 base-excision repair enzyme: concerted effect of Lys249 and Asp268 during excision of 8-oxoguanine

Šebera, J, Hattori, Y, Sato, D, Reha, D, Nencka, R, Kohno, T, Kojima, C, Tanaka, Y, Sychrovský, V

Nucleic Acids Res. 2017
19537786 The R46Q, R131Q and R154H polymorphs of human DNA glycosylase/beta-lyase hOgg1 severely distort the active site and DNA recognition site but do not cause unfolding

Anderson, PC, Daggett, V

J. Am. Chem. Soc. 2009
11002420 Leukemic cell line, KG-1 has a functional loss of hOGG1 enzyme due to a point mutation and 8-hydroxydeoxyguanosine can kill KG-1

Hyun, JW, Choi, JY, Zeng, HH, Lee, YS, Kim, HS, Yoon, SH, Chung, MH

Oncogene 2000
10987279 Alterations of the DNA repair gene OGG1 in human clear cell carcinomas of the kidney

Audebert, M, Chevillard, S, Levalois, C, Gyapay, G, Vieillefond, A, Klijanienko, J, Vielh, P, El Naggar, AK, Oudard, S, Boiteux, S, Radicella, JP

Cancer Res. 2000
17426120 Identification and characterization of OGG1 mutations in patients with Alzheimer's disease

Mao, G, Pan, X, Zhu, BB, Zhang, Y, Yuan, F, Huang, J, Lovell, MA, Lee, MP, Markesbery, WR, Li, GM, Gu, L

Nucleic Acids Res. 2007
9331411 The critical active-site amine of the human 8-oxoguanine DNA glycosylase, hOgg1: direct identification, ablation and chemical reconstitution

Nash, HM, Lu, R, Lane, WS, Verdine, GL

Chem. Biol. 1997
24632493 hOGG1-Cys326 variant cells are hypersensitive to DNA repair inhibition by nitric oxide

Moritz, E, Pauly, K, Bravard, A, Hall, J, Radicella, JP, Epe, B

Carcinogenesis 2014
22451681 Repair of oxidative DNA damage is delayed in the Ser326Cys polymorphic variant of the base excision repair protein OGG1

Kershaw, RM, Hodges, NJ

Mutagenesis 2012
10497264 Excision of oxidatively damaged DNA bases by the human alpha-hOgg1 protein and the polymorphic alpha-hOgg1(Ser326Cys) protein which is frequently found in human populations

Dherin, C, Radicella, JP, Dizdaroglu, M, Boiteux, S

Nucleic Acids Res. 1999
11827746 Radiation sensitivity depends on OGG1 activity status in human leukemia cell lines

Hyun, JW, Cheon, GJ, Kim, HS, Lee, YS, Choi, EY, Yoon, BH, Kim, JS, Chung, MH

Free Radic. Biol. Med. 2002
Participants
Participant Of
Normal reaction
Disease
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
Alzheimer's disease 10652 AD, Alzheimers dementia, Alzheimer disease
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