Meta-Biol

• Pathways

The majority of OGG1 mutants have been tested for 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.

Germline and somatic defects in genes that encode proteins that participate in DNA repair give rise to genetic instability that can lead to malignant transformation or trigger cellular senescence or apoptosis. Germline defects in DNA repair genes are an underlying cause of familial cancer syndromes and premature ageing syndromes. Somatic defects in DNA repair genes are frequently found in tumors. For review, please refer to Tiwari and Wilson 2019.

We have so far annotated diseases of mismatch repair, diseases of base excision repair and diseases of DNA double-strand break repair.

Defects in mammalian DNA mismatch repair (MMR) genes (MLH1, PMS2, MSH2, and MSH6) result in microsatellite instability (MSI) and reduced fidelity during replication and repair steps. Defective variants of MMR genes are associated with sporadic cancers with hypermutation phenotypes as well as hereditary cancer syndromes such as Lynch syndrome (hereditary non-polyposis colorectal cancer) and constitutional mismatch repair deficiency syndrome (CMMRD). MSI is an important predictor of sensitivity to cancer immunotherapy as the high mutational burden renders MSI tumors immunogenic and sensitive to programmed cell death-1 (PD-1) immune checkpoint inhibitors (Mandal et al. 2019). For review, please refer to Pena-Diaz and Rasmussen 2016, Sijmons and Hofstra 2016, Tabori et al. 2017, Baretti and Le 2018.

Germline mutations, single nucleotide polymorphisms (SNPs) and somatic mutations in several genes involved in base excision repair (BER), a DNA repair pathway where a damaged DNA base is excised and replaced with a correct base, are involved in the development of cancer and several oxidative stress-related diseases. For review, please refer to Fu et al. 2012, Fletcher and Houlston 2010, Brenerman et al. 2014, Patrono et al. 2014, and D'Errico et al. 2017.

Germline mutations in genes involved in repair of DNA double-strand breaks (DSBs) are the underlying cause of several cancer predisposition syndromes, some of which also encompass developmental disorders associated with immune dysfunction, radiosensitivity and neurodegeneration. Somatic mutations in genes involved in DSB repair also occur in sporadic cancers. For review, please refer to McKinnon and Caldecott 2007, Keijzers et al. 2017, and Jachimowicz et al. 2019.

Biological processes are captured in Reactome by identifying the molecules (DNA, RNA, protein, small molecules) involved in them and describing the details of their interactions. From this molecular viewpoint, human disease pathways have three mechanistic causes: the inclusion of microbially-expressed proteins, altered functions of human proteins, or changed expression levels of otherwise functionally normal human proteins.

The first group encompasses the infectious diseases such as influenza, tuberculosis and HIV infection. The second group involves human proteins modified either by a mutation or by an abnormal post-translational event that produces an aberrant protein with a novel function. Examples include somatic mutations of EGFR and FGFR (epidermal and fibroblast growth factor receptor) genes, which encode constitutively active receptors that signal even in the absence of their ligands, or the somatic mutation of IDH1 (isocitrate dehydrogenase 1) that leads to an enzyme active on 2-oxoglutarate rather than isocitrate, or the abnormal protein aggregations of amyloidosis which lead to diseases such as Alzheimer's.

Infectious diseases are represented in Reactome as microbial-human protein interactions and the consequent events. The existence of variant proteins and their association with disease-specific biological processes is represented by inclusion of the modified protein in a new or variant reaction, an extension to the 'normal' pathway. Diseases which result from proteins performing their normal functions but at abnormal rates can also be captured, though less directly. Many mutant alleles encode proteins that retain their normal functions but have abnormal stabilities or catalytic efficiencies, leading to normal reactions that proceed to abnormal extents. The phenotypes of such diseases can be revealed when pathway annotations are combined with expression or rate data from other sources.

Depending on the biological pathway/process immediately affected by disease-causing gene variants, non-infectious diseases in Reactome are organized into diseases of signal transduction by growth factore receptors and second messengers, diseases of mitotic cell cycle, diseases of cellular response to stress, diseases of programmed cell death, diseases of DNA repair, disorders of transmembrane transporters, diseases of metabolism, diseases of immune system, diseases of neuronal system, disorders of developmental biology, disorders of extracellular matrix organization, and diseases of hemostatis.