DR-GAS: A database of functional genetic variants and their phosphorylation states in human DNA repair systems
Graphical abstract
Introduction
DNA repair is a very complex and vital process through which a cell recognizes damage to the DNA caused by endogenous or environmental insults, as well as genetic defects that result in incomplete repair. The cell tries to repair these damages to retain the integrity of their genome. DNA repair is present in both prokaryotes and eukaryotes, whereas in the later the genome and the repair mechanisms are much more complex [1]. Various factors involved for incorporating changes or aberrations in DNA molecule such as reactive oxygen species [2], replication errors, ultraviolet radiations, X-rays, gamma rays, thermal disruption and viruses can all result in the DNA damage [3]. There is a high rate of recurrence for endogenous DNA damage as compared to exogenous damage and the type of damages produced due to both factors is roughly indistinguishable [4]. The damage to the DNA is caused by multiple factors such as oxidation of bases, generation of DNA strand interruptions, alkylation of bases [5], bulky adduct formation, mismatches and pyrimidine dimers that often trigger viral interactions [6].
The elimination of damaged DNA from the genome is a complicated process involving a number of repair proteins like DDB2, MLH1, XPA and different associated mechanisms for diverse type of lesions. The numerous known mechanisms by which the damaged DNA is repaired includes BER, NER, MMR, HRR, NHEJ, DDS and TLS which have different set of genes, enzymes and pathways for repairing the DNA. These mechanisms not only maintain the genetic stability but also prevent the genome from carcinogenesis, pre-mature aging, cockayne syndrome, xeroderma pigmentosum, progeria and several other disorders [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20] which we are intended to analyze in this study for better understanding of the entire process.
Innumerable genetic sequence patterns comprising of common haplotype blocks, essential genetic markers and LD plots are associated with DNA repair related disorders, where some of the DNA repair genes have already been analyzed for its strong involvement with the genetic diseases. The XRCC1 DNA repair gene is said to be involved in pancreatic cancer and its haplotype analysis showed a strong statistical association with the disorder [21]. Saadat et al. [22] demonstrated that preeclampsia disorder is linked with higher frequency of “194R-399Q” haplotype in XRCC1 gene with a confidence of 95% as compared to the control. Moreover, variations in ERCC5 repair gene have been reported in gastric cancer which serves as an important marker for the disease [23]. Similar studies on ERCC1 and ERCC2 DNA repair genes were performed to prominently demonstrate the association of the two genes with lung adenocarcinoma [24]. Above mentioned studies suggest the involvement and association of LD and common haplotype patterns with countless DNA repair disorders [25]. Therefore, there is a need to analyze these indispensible genetic parameters in an efficient way to understand the mechanisms of DNA repair related disorders.
The intrinsic properties of many DNA repair proteins are found to be affected by the altered phosphorylation sites, since its state may govern the risk of developing cancers [26], [27], [28]. The phosphorylation takes place at serine (S), threonine (T) or tyrosine (Y) residues [29] in the proteins which not only influences the structure but also affects the function, stability, sub-cellular localizations and interaction with other proteins [30], [31]. Few cases of key DNA repair proteins, where nsSNPs such as S31R (CDKN1A), S326C (OGG1) and T241M (XRCC3) have already been associated with risks for endometrial [32], esophageal [33], [34], lung [35] and breast cancers [36] due to change in their phosphorylation states. The change may be from phosphorylated to dephosphorylated residue or vice-versa affecting the activity of the repair proteins. The change due to nsSNPs in DNA repair proteins is also found to be defensive against certain disorders, for example T241M mutation in XRCC3 protein is protective against bladder cancer in heavy smokers [37]. Since, the phosphorylation states play an imperative role in the regulation of multitude of cellular processes, gene expression, signal transduction, apoptosis, homeostasis and DNA damage recognition and its repair [38], it is important to thoroughly analyze the phosphorylation states of diverse DNA repair proteins.
In human molecular systems, DNA repair is a very crucial process for which the main challenge lies in the development of a platform where one could easily access and retrieve the integrated information for several genetic parameters involved in DNA repair. Currently, not many resources are available which provide information on DNA repair. Few such resources are REPAIRtoire [39] and Repair funmap [40], while to the best of our knowledge there is no database till date which provides all the information associated with genetic parameters of human DNA repair system in a comprehensive way. Additionally, none of the available resources provide information concerning the functional association of nsSNPs and their phosphorylation states for human DNA repair system.
Keeping in view all the above mentioned requirements and to fill up this research gap for DNA repair systems, first a widespread computational analysis on the genotype data was performed and then a database named, DR-GAS (DNA Repair Genetic Association Studies) was compiled for various genetic features, for instance haplotype blocks, LD plots, essential genetic markers and their respective statistical parameters. This database also includes nsSNPs and their putative functional effect on the genome through their phosphorylation states amongst all DNA repair mechanisms. DR-GAS database is a unique and most comprehensive database regarding DNA repair genes which include their involvement in various repair mechanisms, associated pathways and diseases which could be of utmost use to the researchers involved in the study of DNA repair.
Section snippets
Materials and methods
In this study, we applied an integrated approach which is a combination of in silico and quantitative genetic studies, being performed on 215 DNA repair genes, their proteins, associated pathways, diseases, etc., obtained from NCBI and other published studies. On the basis of literature and information collected from numerous relevant resources, we categorized all DNA repair genes into major 16 classes as shown in Fig. 1.
Results and discussions
In this study, 215 DNA repair genes are categorized on the basis of the mechanisms in which they are involved. DR-GAS database provides an easy and effective way for the search and retrieval of genetic essential markers and associated information for repair genes as shown in Fig. 2. We have collected the LD, haplotype, markers, nsSNPs, pathways and disease related information for 215 repair genes which have been classified into main pathways such as BER, NER, MMR, HRR, NHEJ, DDS, TLS, DNA
Conclusion
DR-GAS is a compendium and comprehensive resource of DNA repair genes, their association studies with disease, other genetic parameters and phosphorylation states. There is no such catalog for DNA repair genes available which provides all these essential quantitative genetic details including LD, haplotype, SNPs, disease related information, and their phosphorylation states on a common platform. This database will help the researchers or scientists to study the repair genes in depth and will
Conflict of interest statement
The Authors declare that there are no conflicts of interest.
Acknowledgements
We would like to express our gratitude to the editor and two anonymous reviewers whose constructive and insightful comments were very helpful in strengthening this paper. We thank Priya P. Panigrahi for critically reading the manuscript. This work was funded by Department of Science and Technology (DST), India through FASTTRACK Scheme grant (SR/FT/LS-026/2009) to TRS.
References (52)
- et al.
Recombination at double-strand breaks and DNA ends: conserved mechanisms from phage to humans
Mol. Cell.
(2001) - et al.
The interacting pathways for prevention and repair of oxidative DNA damage
Mutat. Res.
(2003) - et al.
The contribution of endogenous sources of DNA damage to the multiple mutations in cancer
Mutat. Res.
(2001) - et al.
Using or abusing: viruses and the cellular DNA damage response
Trends Microbiol.
(2007) - et al.
Diseases with DNA damage-processing defects
Am. J. Med. Sci.
(1988) - et al.
Fanconi anemia and Bloom's syndrome crosstalk through FANCJ-BLM helicase interaction
Trends Genet.
(2012) - et al.
Promoter polymorphisms in DNA repair gene ERCC5 and susceptibility to gastric cancer in Chinese
Gene
(2012) - et al.
HapMap-based study of a region encompassing ERCC1 and ERCC2 related to lung cancer susceptibility in a Chinese population
Mutat. Res.
(2011) An overview of the mechanisms of mutagenesis and carcinogenesis
Mutat. Res.
(2003)- et al.
The mammalian XRCC genes: their roles in DNA repair and genetic stability
DNA Rep. (Amst)
(2003)
DNA damage tumor suppressor genes and genomic instability
Curr. Opin. Genet. Dev.
Control by phosphorylation
Curr. Opin. Struct. Biol.
The regulation of protein function by multisite phosphorylation–a 25 year update
Trends Biochem. Sci.
Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems
Cell
p53 and p21 genetic polymorphisms and susceptibility to endometrial cancer
Gynecol. Oncol.
Association between p21 codon 31 polymorphism and esophageal cancer risk in a Taiwanese population
Cancer Lett.
Protein phosphorylation and signal transduction
Pharmacol. Ther.
Sequence- and structure-based prediction of eukaryotic protein phosphorylation sites
J. Mol. Biol.
GeneCards: integrating information about genes, proteins and diseases
Trends Genet.
Viruses and apoptosis
Annu. Rev. Microbiol.
DNA repair enzymes
Annu. Rev. Biochem.
DNA repair mechanisms protect our genome from carcinogenesis
Front. Biosci.
Rare hereditary diseases with defects in DNA-repair
Eur. J. Dermatol.
Nuclear DNA damage as a direct cause of aging
Rejuven. Res.
DNA damage, aging, and cancer
N. Engl. J. Med.
Molecular signaling mechanisms of apoptosis in hereditary non-polyposis colorectal cancer
World J. Gastrointest. Pathophysiol.
Cited by (6)
Novel structural and functional impact of damaging single nucleotide polymorphisms (SNPs) on human SMYD2 protein using computational approaches
2021, Meta GeneCitation Excerpt :Among the SNPs, non-synonymous SNPs (nsSNPs) are accountable to alter the protein functions that may lead to cause diverse human diseases (Chitrala and Yeguvapalli 2014; Jia et al. 2014; Sehgal and Singh 2014a). In the recent past, nsSNPs in cancer-associated genes have received great interest (Sehgal and Singh 2014b). Various computational screening and molecular dynamics simulation studies of cancer-associated nsSNPs in many genes were performed (Chitrala and Yeguvapalli 2014; Islam et al. 2019; Kumar and Purohit 2014; Wang et al. 2019).
Hydroxymethylation and its potential implication in DNA repair system: A review and future perspectives
2015, GeneCitation Excerpt :DNA repair itself is a convoluted process involving myriad of proteins, interactions and pathways to recognize and repair the damages occurring in genome due to intrinsic or environmental factors. Although, the process of DNA repair has already been extensively studied for its role in diverse form of cancers, and neurological diseases (Gehring et al., 2009; Panigrahi and Singh, 2013; Sehgal and Singh, 2014a, 2014b), less attention has been paid on its role for demethylation of DNA. DNA repair is a mechanism for active DNA demethylation and also there are indications that these repair pathways, especially, BER is involved in the loss of paternal DNA methylation in zygote.
Systems biology approach for mutational and site-specific structural investigation of DNA repair genes for xeroderma pigmentosum
2014, GeneCitation Excerpt :The phenotypic changes caused by these variations have been shown in Supp. Table 1. More details about DNA repair mechanisms and other associated details could be found at our recently published database (Sehgal and Singh, 2014). The variations in NER related genes caused changes in the expression, functions and their important roles in the repair mechanism.
Fundamental and Best Practices for Protein Annotations
2023, Bioinformatics and Computational Biology: Technological Advancements, Applications and OpportunitiesComputational studies to explore the role of MSI associated DNA mismatch repair mechanisms in HNPCC through expression and interaction data
2020, International Journal of Bioinformatics Research and Applications
- 1
DNA Repair-Genetic Association Studies.