OGG1 missense mutants OGG1 R46Q (Audebert, Chevillard et al....

created [InstanceEdit:9656310] Orlic-Milacic, Marija, 2019-07-31
dbId 9656309
displayName OGG1 missense mutants OGG1 R46Q (Audebert, Chevillard et al....
literatureReference
modified [InstanceEdit:9664207] Orlic-Milacic, Marija, 2019-10-21
schemaClass Summation
text 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.
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