Elsevier

DNA Repair

Volume 16, April 2014, Pages 97-103
DNA Repair

DR-GAS: A database of functional genetic variants and their phosphorylation states in human DNA repair systems

https://doi.org/10.1016/j.dnarep.2014.01.004Get rights and content

Highlights

  • The most comprehensive quantitative genetic study on DNA repair genes and proteins.

  • Computational identification of phosphorylation sites in human DNA repair genes.

  • Detection of nsSNPs and their functional effect on human DNA repair systems.

  • Extensive compilation of disease and pathways associated with human repair systems.

  • Unique repository on haplotypes, LD, phosphorylation sites of human repair systems.

Abstract

We present DR-GAS1, a unique, consolidated and comprehensive DNA repair genetic association studies database of human DNA repair system. It presents information on repair genes, assorted mechanisms of DNA repair, linkage disequilibrium, haplotype blocks, nsSNPs, phosphorylation sites, associated diseases, and pathways involved in repair systems. DNA repair is an intricate process which plays an essential role in maintaining the integrity of the genome by eradicating the damaging effect of internal and external changes in the genome. Hence, it is crucial to extensively understand the intact process of DNA repair, genes involved, non-synonymous SNPs which perhaps affect the function, phosphorylated residues and other related genetic parameters. All the corresponding entries for DNA repair genes, such as proteins, OMIM IDs, literature references and pathways are cross-referenced to their respective primary databases. DNA repair genes and their associated parameters are either represented in tabular or in graphical form through images elucidated by computational and statistical analyses. It is believed that the database will assist molecular biologists, biotechnologists, therapeutic developers and other scientific community to encounter biologically meaningful information, and meticulous contribution of genetic level information towards treacherous diseases in human DNA repair systems. DR-GAS is freely available for academic and research purposes at: http://www.bioinfoindia.org/drgas.

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.

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