To Study The Molecular Characterization Of X-Ray Cross-Complementing Group 1 (Xrcc1) Gene And 8-Oxoguanine Glycosylase-1 (Ogg1) Gene With Its Associated Risk Factors In Senile Cataract Patients: As A Marker For The Dna Repair Protein
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Abstract
Cataract is the opacity of the natural human lens, which may be resulted from congenital, developmental and acquired causes.[1]. Cataract is the leading causes of blindness worldwide, which accounts about more than half of 39 million blind people worldwide. WHO estimates1-2 million people go blind yearly. Every 5sec 1 person, every minute a child goes blind in the world [2].
Cataract is the leading cause of blindness all over the world, responsible for 47.8% of blindness and accounting for 17.7 million blind people [3]. In India, 80% of the blindness is due to cataract [4]. Various modifiable risk factors associated with cataract include UV exposure, diabetes, hypertension, body mass index (BMI), drug usage, smoking and socioeconomic factors; but advancing age is the single most important risk factor for cataract [5-7].
India has a higher prevalence of cataracts than the West [3, 4]. People with severe hypertension are more prone to develop cataracts, and hypertension has been linked to cataract formation [5]. Risk factors for presenile cataract were smoking, atopic dermatitis, high myopia, diabetes mellitus, and industrial metal work exposure. Cataracts in patients with diabetes mellitus (DM) are also associated with age and duration of disease [7].
DNA repair enzymes perform a vital function in continuously monitoring chromosomes to rectify damaged nucleotide residues caused by exposure to carcinogens and cytotoxic chemicals [8]. Polymorphisms in DNA repair genes reduced their ability to repair DNA damage, making the human body much more susceptible to cancer and age-related disorders [9, 10]. Base excision repair (BER) is one of the most important DNA repair processes. X-ray repair cross-complementing protein 1(XRCC1) is DNA repair protein. In human this protein is encoded by XRCC1 gene. Wherever DNA repair is complexes with DNA ligase III XRCC1 also involved. The XRCC1 marks a good biomarker and the association between 8-oxoguanine glycosylase-1(OGG1), AP endonuclease-1 (APE1) and X-ray repair cross-complementing-1 (XRCC1) genes polymorphisms and age-related macular degeneration, pterygium and onset primaryopen-angle glaucoma have been studied [11,12].
Patients' cataracts are primarily caused by the X-ray cross-complementing group 1 (XRCC1), a DNA repair protein involved in single-strand breaks (SSBs) and the BER pathway. It has been reported that this protein effectively repairs DNA damage brought on by active oxygen, ionization, and alkylating agents [13]. To fix SSBs found at codons 194 (Arg-Trp), 280 (Arg-His), and 399 (Arg-Gln), three primary enzymes are needed: DNA ligase III, DNA polymerase β, and poly-ADP-ribose polymerase (PARP). The most prevalent XRCC1 gene polymorphism was discovered at codon Arg399Gln, which is caused by a nucleotide alteration from guanine to adenine in the PARP binding domain. This substitution may have an impact on the effectiveness of complex formation or repair .
Exposure to ionising radiation and alkylating chemicals causes DNA single-strand breaks, which are rapidly repaired by XRCC1. The XRCC1 protein interacts with DNA ligase III, polymerase beta, and poly(ADP-ribose) polymerase to engage in the base excision repair pathway. It plays a vital role in DNA processing during recombination in germ cells and meiogenesis. The XRCC1 protein works as a scaffolding protein in the process, interacting with different repair enzymes and acting accordingly. Repair enzymes (XRCC1) need scaffolding to carry out their enzymatic steps in DNA repair. XRCC1 plays an important part in single-strand break repair, base excision repair, and nucleotide excision repair.Oxoguanine glycosylase (OGG1) is a glycosylase enzyme; it is encoded by the OGG1gene in human. It is also involve in base excision repair mechanism. It is found in bacterial, and eukaryotic species.Due to the exposure to reactive oxygen species (ROS) a mutagenic byproduct occurs that is 8-oxoguanine, and for excision of 8-oxoG OGG1 is primary enzyme. OGG1 is a bifunctional glycosylase, OGG1 is able to cleave the glycosidic bond of the mutagenic lesion and also cause a strand break in the DNA backbone that’s why OGG1 work as a bifunctional glycosylase. Alternative splicing of the C-terminal region of OGG1 gene classifies the splice variants into two major groups, type 1 and type 2, process depending on the last exon of the sequence. Type 1 alternative splice variants end with exon 7 and type 2 end with exon . One set of spliced forms are designated from 1a, 1b, and 2a to 2e. N-terminus of OGG1 gene contains a mitochondrial targeting signal in eukaryotes, it is essential for mitochondrial localization.
The XRCC1 gene and OGG1 gene shows to play a significant impact in patients' associations with cataract risk, which would aid research into the mechanism of DNA repair. The association of 8-oxoguanine glycosylase-1 (OGG1), and X-ray repair cross-complementing-1 (XRCC1) gene plays a critical role in the elevated susceptibility to Age-related cataracts, indicating that this mutation is one of the likely mechanisms that increases the risk of age-related cataracts.
Cataract is the leading cause of blindness all over the world, responsible for 47.8% of blindness and accounting for 17.7 million blind people [3]. In India, 80% of the blindness is due to cataract [4]. Various modifiable risk factors associated with cataract include UV exposure, diabetes, hypertension, body mass index (BMI), drug usage, smoking and socioeconomic factors; but advancing age is the single most important risk factor for cataract [5-7].
India has a higher prevalence of cataracts than the West [3, 4]. People with severe hypertension are more prone to develop cataracts, and hypertension has been linked to cataract formation [5]. Risk factors for presenile cataract were smoking, atopic dermatitis, high myopia, diabetes mellitus, and industrial metal work exposure. Cataracts in patients with diabetes mellitus (DM) are also associated with age and duration of disease [7].
DNA repair enzymes perform a vital function in continuously monitoring chromosomes to rectify damaged nucleotide residues caused by exposure to carcinogens and cytotoxic chemicals [8]. Polymorphisms in DNA repair genes reduced their ability to repair DNA damage, making the human body much more susceptible to cancer and age-related disorders [9, 10]. Base excision repair (BER) is one of the most important DNA repair processes. X-ray repair cross-complementing protein 1(XRCC1) is DNA repair protein. In human this protein is encoded by XRCC1 gene. Wherever DNA repair is complexes with DNA ligase III XRCC1 also involved. The XRCC1 marks a good biomarker and the association between 8-oxoguanine glycosylase-1(OGG1), AP endonuclease-1 (APE1) and X-ray repair cross-complementing-1 (XRCC1) genes polymorphisms and age-related macular degeneration, pterygium and onset primaryopen-angle glaucoma have been studied [11,12].
Patients' cataracts are primarily caused by the X-ray cross-complementing group 1 (XRCC1), a DNA repair protein involved in single-strand breaks (SSBs) and the BER pathway. It has been reported that this protein effectively repairs DNA damage brought on by active oxygen, ionization, and alkylating agents [13]. To fix SSBs found at codons 194 (Arg-Trp), 280 (Arg-His), and 399 (Arg-Gln), three primary enzymes are needed: DNA ligase III, DNA polymerase β, and poly-ADP-ribose polymerase (PARP). The most prevalent XRCC1 gene polymorphism was discovered at codon Arg399Gln, which is caused by a nucleotide alteration from guanine to adenine in the PARP binding domain. This substitution may have an impact on the effectiveness of complex formation or repair .
Exposure to ionising radiation and alkylating chemicals causes DNA single-strand breaks, which are rapidly repaired by XRCC1. The XRCC1 protein interacts with DNA ligase III, polymerase beta, and poly(ADP-ribose) polymerase to engage in the base excision repair pathway. It plays a vital role in DNA processing during recombination in germ cells and meiogenesis. The XRCC1 protein works as a scaffolding protein in the process, interacting with different repair enzymes and acting accordingly. Repair enzymes (XRCC1) need scaffolding to carry out their enzymatic steps in DNA repair. XRCC1 plays an important part in single-strand break repair, base excision repair, and nucleotide excision repair.Oxoguanine glycosylase (OGG1) is a glycosylase enzyme; it is encoded by the OGG1gene in human. It is also involve in base excision repair mechanism. It is found in bacterial, and eukaryotic species.Due to the exposure to reactive oxygen species (ROS) a mutagenic byproduct occurs that is 8-oxoguanine, and for excision of 8-oxoG OGG1 is primary enzyme. OGG1 is a bifunctional glycosylase, OGG1 is able to cleave the glycosidic bond of the mutagenic lesion and also cause a strand break in the DNA backbone that’s why OGG1 work as a bifunctional glycosylase. Alternative splicing of the C-terminal region of OGG1 gene classifies the splice variants into two major groups, type 1 and type 2, process depending on the last exon of the sequence. Type 1 alternative splice variants end with exon 7 and type 2 end with exon . One set of spliced forms are designated from 1a, 1b, and 2a to 2e. N-terminus of OGG1 gene contains a mitochondrial targeting signal in eukaryotes, it is essential for mitochondrial localization.
The XRCC1 gene and OGG1 gene shows to play a significant impact in patients' associations with cataract risk, which would aid research into the mechanism of DNA repair. The association of 8-oxoguanine glycosylase-1 (OGG1), and X-ray repair cross-complementing-1 (XRCC1) gene plays a critical role in the elevated susceptibility to Age-related cataracts, indicating that this mutation is one of the likely mechanisms that increases the risk of age-related cataracts.
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