BioPAX pathway converted from "Defective OGG1 Substrate Processing" in the Reactome database. Defective OGG1 Substrate Processing Defective OGG1 Substrate Processing 大多数OGG1突变体检测their ability to excise 8-oxoguanine (8oxoG) from damaged DNA, while a small number of mutants have been tested for the ability to remove FapyG from DNA.
The following OGG1 mutants show at least a partial loss of their ability to remove 8oxoG:
OGG1 R46Q (Audebert, Chevillard et al. 2000; Audebert, Radicella et al. 2000);
OGG1 R154H (Audebert, Radicella et al. 2000, Bruner et al. 2000);
OGG1 R131Q (Chevillard et al. 1998, Bruner et al. 2000, Anderson and Dagget 2009);
OGG1 R229Q (Hyun et al. 2000, Hyun et al. 2002, Hill and Evans 2007);
OGG1 P266fs139* (Mao et al. 2007).
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, a frequent variant in European and Asian populations, is susceptible to oxidation, which diminishes catalytic activity under conditions of oxidative stress (Dherin et al. 1999, Yamane et al. 2004, Kershaw and Hodges 2012, Moritz et al. 2014).
The following OGG1 mutants show at least a partial loss of their ability to remove FapyG:
OGG1 R46Q (Audebert, Radicella et al. 2000);
OGG1 R154H (Audebert, Radicella et al. 2000).
OGG1 R46L has not been functionally studied but has been reported in cancer and predicted to be pathogenic. It is annotated as a candidate disease variant for FapyG excision, based on its similarity with OGG1 R46Q. Authored: Orlic-Milacic, Marija, 2019-07-30 Reviewed: Vlahopoulos, Spiros, 2019-10-02 Reviewed: Boldogh, Istvan, 2019-10-08 Edited: Orlic-Milacic, Marija, 2019-10-10 OGG1 S326C is oxidized OGG1 S326C is oxidized OGG1 S326C是一个频繁的遗传多态性,前sent in more than 20% of people of European and Asian descent (Janssen et al. 2001, Moritz et al. 2014). On its own, substitution of serine with cysteine at position 326 does not affect the catalytic activity of OGG1 (Dherin et al. 1999, Janssen et al. 2001, Moritz et al. 2014). However, under oxidative stress, OGG1 S326C variant is more susceptible to oxidation or nitrosation than the wild type enzyme (Moritz et al. 2014), which diminishes catalytic activity and leads to accumulation of genomic 8-oxoguanine (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 and FapyG (Dherin et al. 1999).
The frequency of OGG1 S326C allele is increased in NSCLC patients and the level of 8-oxodG is higher in lung tissue and leukocytes of these patients (Janik et al. 2011). OGG1 S326C variant is associated with an increased breast cancer risk (Ali et al. 2015). Authored: Orlic-Milacic, Marija, 2019-07-30 Reviewed: Vlahopoulos, Spiros, 2019-10-02 Reviewed: Boldogh, Istvan, 2019-10-08 Edited: Orlic-Milacic, Marija, 2019-10-10 Reactome DB_ID: 9658769 1 nucleoplasm GO 0005654 UniProt:O15527 OGG1 OGG1 MUTM OGH1 OGG1 MMH FUNCTION DNA repair enzyme that incises DNA at 8-oxoG residues. Excises 7,8-dihydro-8-oxoguanine and 2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine (FAPY) from damaged DNA. Has a beta-lyase activity that nicks DNA 3' to the lesion.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the type-1 OGG1 family. Reactome //www.joaskin.com Homo sapiens NCBI Taxonomy 9606 UniProt O15527 l-serine 326 replaced with L-cysteine 326 EQUAL l-serine removal [MOD:01646] Chain Coordinates 1 EQUAL 345 EQUAL Reactome DB_ID: 3785707 1 reactive oxygen species [ChEBI:26523] reactive oxygen species ChEBI 26523 Reactome DB_ID: 9658815 1 l-serine 326 replaced with L-cysteine 326 EQUAL l-cysteine sulfenic acid at 326 326 EQUAL l-cysteine sulfenic acid 1 EQUAL 345 EQUAL Reactome Database ID Release 77 9658813 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9658813 Reactome R-HSA-9658813 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9658813.1 21376741 Pubmed 2011 8-Oxoguanine incision activity is impaired in lung tissues of NSCLC patients with the polymorphism of OGG1 and XRCC1 genes Janik, Justyna Swoboda, Maja Janowska, Beata Cieśla, Jarosław M Gackowski, Daniel Kowalewski, Janusz Olinski, Ryszard Tudek, Barbara Speina, Elżbieta Mutat. Res. 709:21-31 26089588 Pubmed 2015 OGG1 Mutations and Risk of Female Breast Cancer: Meta-Analysis and Experimental Data Ali, Kashif Mahjabeen, Ishrat Sabir, Maimoona Mehmood, Humera Kayani, Mahmood Akhtar Dis. Markers 2015:690878 24632493 Pubmed 2014 hOGG1-Cys326 variant cells are hypersensitive to DNA repair inhibition by nitric oxide Moritz, Eva Pauly, Karin Bravard, Anne Hall, Janet Radicella, J Pablo Epe, Bernd Carcinogenesis 35:1426-33 Defective OGG1 mutants do not excise 8-oxoguanine Defective OGG1 mutants do not excise 8-oxoguanine 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. Authored: Orlic-Milacic, Marija, 2019-07-30 Reviewed: Vlahopoulos, Spiros, 2019-10-02 Reviewed: Boldogh, Istvan, 2019-10-08 Edited: Orlic-Milacic, Marija, 2019-10-10 Reactome DB_ID: 9656301 1 OGG1 mutants:(8oxoG:Cyt)-dsDNA [nucleoplasm] OGG1 mutants:(8oxoG:Cyt)-dsDNA Reactome DB_ID: 110184 1 (8oxoG:Cyt)-dsDNA [nucleoplasm] (8oxoG:Cyt)-dsDNA Double-strand DNA containing an 8-oxo guanine opposite to a cytosine Converted from EntitySet in Reactome Reactome DB_ID: 9656300 1 OGG1 mutants (8oxoG hydrolysis) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity OGG1 D268N [nucleoplasm] OGG1 R46Q [nucleoplasm] OGG1 D268A [nucleoplasm] OGG1 R131Q [nucleoplasm] OGG1 P266fs139* [nucleoplasm] OGG1 K249Q [nucleoplasm] OGG1 R229Q [nucleoplasm] SOH-C326-OGG1 S326C [nucleoplasm] OGG1 R154H [nucleoplasm] Reactome Database ID Release 77 9656301 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9656301 Reactome R-HSA-9656301 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9656301.1 Reactome Database ID Release 77 9656250 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9656250 Reactome R-HSA-9656250 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9656250.1 17651912 Pubmed 2007 A novel R229Q OGG1 polymorphism results in a thermolabile enzyme that sensitizes KG-1 leukemia cells to DNA damaging agents Hill, Jeff W Evans, Michele K 癌症检测。Prev 31:237-43。 12578369 Pubmed 2003 Structural and biochemical exploration of a critical amino acid in human 8-oxoguanine glycosylase Norman, Derek P G Chung, SJ Verdine, GL Biochemistry 42:1564-72 22451681 Pubmed 2012 Repair of oxidative DNA damage is delayed in the Ser326Cys polymorphic variant of the base excision repair protein OGG1 Kershaw, Rachael M Hodges, Nikolas J Mutagenesis 27:501-10 11902834 Pubmed 2002 Reciprocal "flipping" underlies substrate recognition and catalytic activation by the human 8-oxo-guanine DNA glycosylase Bjørås, Magnar Seeberg, Erling luna, Luisa Pearl, Laurence H Barrett, Tracey E J. Mol. Biol. 317:171-7 10908322 Pubmed 2000 Effect of single mutations in the OGG1 gene found in human tumors on the substrate specificity of the Ogg1 protein Audebert, M Radicella, J P Dizdaroglu, M Nucleic Acids Res. 28:2672-8 11002420 Pubmed 2000 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, J W Choi, J Y Zeng, H H lee, Y S Kim, H S Yoon, S H Chung, M H Oncogene 19:4476-9 9331411 Pubmed 1997 The critical active-site amine of the human 8-oxoguanine DNA glycosylase, hOgg1: direct identification, ablation and chemical reconstitution Nash, H M lu, R lane, WS Verdine, G L Chem. Biol. 4:693-702 17426120 Pubmed 2007 Identification and characterization of OGG1 mutations in patients with Alzheimer's disease Mao, Guogen 锅,小雨 Zhu, Bei-Bei Zhang, Yanbin Yuan, Fenghua Huang, Jian lovell, Mark A lee, Maxwell P Markesbery, William R li, Guo-Min Gu, Liya Nucleic Acids Res. 35:2759-66 19537786 Pubmed 2009 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, Peter C Daggett, Valerie J. Am. Chem. Soc. 131:9506-15 9662341 Pubmed 1998 Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours Chevillard, S Radicella, J P levalois, C lebeau, J Poupon, M F Oudard, S Dutrillaux, B Boiteux, S Oncogene 16:3083-6 10706276 Pubmed 2000 Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA Bruner, S D Norman, D P Verdine, G L Nature 403:859-66 11827746 Pubmed 2002 Radiation sensitivity depends on OGG1 activity status in human leukemia cell lines Hyun, Jin-Won Cheon, Gi-Jeong Kim, Hyun-Sook lee, Yun-Sil Choi, Eun-Young Yoon, Byung-Hak Kim, Jeong-Soon Chung, Myung-Hee Free Radic. Biol. Med. 32:212-20 28334993 Pubmed 2017 The mechanism of the glycosylase reaction with hOGG1 base-excision repair enzyme: concerted effect of Lys249 and Asp268 during excision of 8-oxoguanine Šebera, Jakub Hattori, Yoshikazu Sato, Daichi Reha, David Nencka, Radim Kohno, Takashi Kojima, Chojiro Tanaka, Yoshiyuki Sychrovský, Vladimír Nucleic Acids Res. 45:5231-5242 30311374 Pubmed 2018 ClinGen Allele Registry links information about genetic variants Pawliczek, Piotr Patel Ronak Y Ashmore, Lillian R Jackson, Andrew R Bizon, Chris Nelson, Tristan Powell, Bradford Freimuth, RR Strande, Natasha Shah, Neethu Paithankar, Sameer Wright, Matt W Dwight, Selina Zhen, Jimmy landrum, Melissa McGarvey, Peter Babb, Larry Plon, Sharon E Milosavljevic, Aleksandar Clinical Genome (ClinGen) Resource, - Hum. Mutat. 39:1690-1701 10987279 Pubmed 2000 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, A K Oudard, S Boiteux, S Radicella, J P Cancer Res. 60:4740-4 10497264 Pubmed 1999 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, J P Dizdaroglu, M Boiteux, S Nucleic Acids Res. 27:4001-7 Defective OGG1 mutants do not excise FapyG Defective OGG1 mutants do not excise FapyG OGG1 R46Q mutant, reported in renal carcinoma, and OGG1 R154H mutant, reported in stomach cancer cell line MKN4 (Bruner et al. 2000), show decreased excision of FapyG from dsDNA (Audebert, Radicella et al. 2000), with the function of OGG1 R154H being more severely impaired. It is uncertain whether binding to FapyG in dsDNA substrate is affected in OGG1 R46Q and OGG1 R154H.
OGG1 R46L has not been functionally studied but has been reported in cancer and predicted to be pathogenic. It is annotated as a candidate disease variant based on its similarity with OGG1 R46L.
OGG1 S326C is a frequent genetic polymorphism in people of European and Asian descent. OGG1 S326C variant is susceptible to oxidative modifications, leading to diminished catalytic activity (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 FapyG (Dherin et al. 1999). Authored: Orlic-Milacic, Marija, 2019-07-30 Reviewed: Vlahopoulos, Spiros, 2019-10-02 Reviewed: Boldogh, Istvan, 2019-10-08 Edited: Orlic-Milacic, Marija, 2019-10-10 Reactome DB_ID: 9657134 1 OGG1 mutants:FapyG-dsDNA [nucleoplasm] OGG1 mutants:FapyG-dsDNA OGG1 R46Q,OGG1 R154H,SOH-C326-OGG1 S326C,(OGG1 R46L):FapyG-dsDNA OGG1 R46Q,OGG1 R154H,SOH-C326-OGG1 S326C,(OGG1 R46L):formamidopyrimidine complex Reactome DB_ID: 110182 1 FapyG-dsDNA [nucleoplasm] FapyG-dsDNA Double-strand DNA containing 2,6-diamino-4-hydroxy-5-formamido-pyrimidine Converted from EntitySet in Reactome Reactome DB_ID: 9657137 1 OGG1 mutants (FapyG hydrolysis) [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity OGG1 R46Q [nucleoplasm] SOH-C326-OGG1 S326C [nucleoplasm] OGG1 R154H [nucleoplasm] Reactome Database ID Release 77 9657134 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9657134 Reactome R-HSA-9657134 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9657134.1 Reactome Database ID Release 77 9656252 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9656252 Reactome R-HSA-9656252 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9656252.1 15073047 Pubmed 2004 Differential ability of polymorphic OGG1 proteins to suppress mutagenesis induced by 8-hydroxyguanine in human cell in vivo Yamane, Arito Kohno, Takashi 伊藤浩平表示 Sunaga, Noriaki Aoki, Kazunori Yoshimura, Kimio Murakami, Hirokazu Nojima, Yoshihisa Yokota, Jun Carcinogenesis 25:1689-94 Reactome Database ID Release 77 9656256 Database identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9656256 Reactome R-HSA-9656256 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9656256.1