DNA Repair Mechanism in Sustenance of Life

Jyotsna Setty
Jyotsna Setty

Genetic information is continually being attacked by extrinsic and intrinsic damaging agents, including atmospheric radiation, chemotherapeutics, reactive oxygen species and, environmental chemicals. If DNA modifications continue, they can affect adversely to the DNA or RNA polymerization, leading to collapse of replication fork or transcription arrest, or can act as mutagenic templates during the synthesis of nucleic acid reactions. To fight with the harmful consequences of DNA damage, organisms have developed complex repair mechanisms that remove aberrant base arrangements or chemical modifications and reimpose the genome to its original state.  


Although genetic variations are important for evolution and also for the survival of the individual demands genetic stability. To maintain genetic stability needs not only an extremely precise DNA replication mechanism, but also repair mechanisms to repair many accidental lesions that continually occur in DNA (Raff et al., 2002). Integration of genome is essential for the survival of an organism and also its proper functioning. Although, DNA is continually subjected to geno-toxic stress which is caused by errors in DNA replication, intrinsic cellular metabolism, as well as radiation and harmful chemicals which is present in drinks, food, tobacco and, drugs. So, cells have developed maintenance mechanisms for damage, repair and preserve fidelity and integrity of genome (Sawicka et al., 2017).

Fault in DNA repair mechanism underlie a number of genetic diseases in human that affect a broad variety of body systems but it also shares a constellation of common traits, primarily a predisposition to cancer (Clancy, 2008). For sustaining genomic integrity and removing the damage of DNA from the genome, organisms have developed intricate interdependent systems that include the DNA-damage response (DDR), and DNA repair mechanisms and, cell cycle check point pathway. This article provide an overview about the major repair mechanisms and their role in resolving of DNA damage. This article will also provides an overview on repairable DNA damage which is produced in reproductive cells of human and the corresponding consequences on infertility. In humans, after fertilization primordial germ cells (PGCs) originates from the epiblast between 8 and 14 cell divisions. Primordial germ cells begin to proliferate after differentiation. However, chronology and  the outcome of this process is different which depends on gender.  In gamete production this fundamental difference is crucial for understanding the susceptibility of female and male gametes to DNA damage and repair mechanisms inherent in the oocyte and spermatozoan (Anais et al., 2018). 


Cancer is a disease that includes a ‘‘multi-hit’’ process in which selective genetic mutations causes unregulated cell growth and loss of control over cell proliferation, and at the end metastasis. Events like indels, point mutations, and rearrangements of chromosome are some genetic changes that could compromise the performance of oncogenes or tumor suppressor, which derives cellular transformation. Consistent with genetics instability underlying carcinogenesis, higher frequencies of mutation have been associated with inherited as well as sporadic cases of disease, which arises from increased infidelity in the replication Machinery (Bębenek et al., 2018, Barbari et al., 2017) 


The mismatch repair (MMR) pathway has a wide reach and is capable for repairing single base mismatches and  also for deletions and a variety of small insertions to the genome (Gavande et al., 2016). The connection between mismatch repair defects and cancer has since enlarged to include ‘‘MMR cancer syndrome’’, which includes sporadic cases of disease and inherited recessive mutations that stem from epigenetic silencing or somatic mutations of MMR genes (Ryan et al., 2017). Regardless of the genetic mechanism or disease nomenclature, disorders which stemming from a mismatch repair defect shows almost exclusively an enhancement in development of cancer, not only of the colon cancer, but also of the stomach cancer, biliary, pancreatic system, urinary tract and endometrium. The mutational event in cells which are deficient in MMR is microsatellite instability (MSI), which is a characteristic that is compatible with the role of mismatch repair in resolving the small indel loops that arise because of polymerase slippage in the repeat sequences. Such microsatellite instability (or repeat length changes) is disclosed via loci-specific PCR which is coupled with capillary gel electrophoresis. On the other hand inactivation of MMR which results in the carcinogenesis, it would seems that the substrates of mismatch repair, i.e., the resulting genomic instability mismatches or small indel loops, are not remarkable contributors to the other pathological outcomes which suggests that these lesions exist in idle state and not interfering with other DNA transactions, like transcription (Zeinalian et al., 2018) 

Base Excision Repair (BER) 

Base Excision Repair represents an attractive target in the therapy of cancer as many of   proteins that involved in the BER have been appeared to be dysregulated in a wide range of cancers (Wallace, 2014). There are a wide variety of different glycosylases that identified the array of the possible modifications of base. Recognition and hydrolysis of  glycosidic bond, which results that abasic site is recognized by APE1 and a nick formed in the abasic site of phosphodiester bond 5′ which results  resulting in 3′ OH and 5′ deoxyribose-phosphate (dRP) termini. Here, the path can diverge and the repair can be completed through long or short patch repair. The long patch base excision repair (LP-BER) occurs by excising at least two nucleotides and DNA synthesis which is catalyzed by pol β or pol δ / ε. In the long repair of the adhesive, the polβ DNA performs the displacement synthesis and as a resuls flap is cut by FEN1 before ligation. Alternatively, the short base excision repair patch (SP-BER) occurs by excising a nucleotide. In short patch repair, the activity of the 5' lyase of the pol β DNA cleaves the 5' dRP and adds a single base before the ligation. However, if the dRP could not be successfull removed the BER pathway which is proceeds through the long-patch mechanism. The LP-BER reconstitution has illustrated an absolute demand for the endo-nuclease activity of FEN1 but it is not required at all for SP-BER. Ligation process is achieved by either DNA ligase I or DNA ligase III in the complex with XRCC1 (Svilar, Goellner, Almeida, & Sobol, 2010).  

APE1 inhibitors 

Altered level or overexpression of AP-endonuclease, APE1 in several cancers has been appeared to enhance the resistance of tumor cells to treatment with numerous chemotherapeutic agents highlighting APE1 as an main target for therapy of cancer (Kaur, Cholia, Mantha, and Kumar, 2014). A organized medicinal chemistry approach directed by the NIH generated N-(3-(benzo[d]thiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c] pyridin-2-yl) acetamide and N-(3-(benzo[d]thiazol-2-yl)-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)acetamide as powerful APE1 inhibitors with the favorable in vitro ADME profile and also appeared good plasma and brain exposure in mouse. 

POL β inhibitors 

POLb is the major gap filling DNA polymerase, almost 30% of solid cancers carry mutations occurs in this gene, predominantly in cases of gastric and colorectal cancer (Wallace et al., 2012). Most of the mutations are somatic but few of them are germline in nature, likeP242R substitution that has been appeared to generate genomic instability. In the catalytic domain of POLb, 135 many of the sporadic mutations occur with the I260M variant reported to shown the impaired fidelity and processivity. Therefore, studies proposed that mutations in POLb can causes inaccurate or inefficient repair, promote genomic instability and resulting cellular transformation which is associated with carcinogenesis (Senejani et al., 2014). 

Neurological Disease 

In aged brains and in pathological brain tissues the accumulation of DNA damage has been reported. In several neurological disorders various DNA repair pathways are known to be dysregulated. However, there is some strong evidence in the literature that is related with the defects in DNA damage repair with various neurological disorders, it is yet unclear whether these all defects are a cause or an effect of the brain pathological (Stein et al., 2017). 

DNA Repair in the Reproductive Cells 

During gametogenesis DNA repair mechanism 

In mammals, gametogenesis is a process where numbers of cell are amplified, meiosis is completed, and haploid cells are structurally and morphologically converted into the sperm oocytes (oogenesis) and (spermiogenesis). Therefore, a complex balance of stability and instability of genome is mandatory which is directed by the interaction of various DNA repair mechanisms. The reproductive cells have an line of DNA repair pathways which involved (a) nucleotide excision repair (NER), (b) mismatch repair, (c) base excision repair (BER), (d) homologous recombination (HR), and (e) non-homologous end joining (NHEJ).

DNA Repair pathway in Male Germ Cells and Spermatozoa 

In terms of recombination there are two main pathways i.e homologous recombination (HR) and non -homologous end joining (NHEJ) seems to have divided their responsibilities on the basis of   cell cycle stage and the nature of the DNA break. Specifically, HR mainly work during S phase of cell cycle and on replication-derived one-ended DSBs to  resolve the damage, on the other hand the more error-prone non-homologous end joining (NHEJ)  process functions mainly during G1 phase of cell cycle (Iyama et al., 2013). 

In the Oocyte DNA Repair Mechanisms 

In mammalian species oocytes are one of the most long-lived cells. Various studies suggested that oocytes, from the primordial follicles stage to that of MII, have the capacity to repair DNA damage and maintain integrity of genome. During the process of oogenesis, genes which are related with DNA repair mechanism are expressed at high levels and their proteins and mRNAs are accumulated inside the oocyte cytoplasm. Transcripts from all repair pathways of DNA involving direct lesion reversal, BER, MMR, NER, HR and NHEJ which are represented in monkey, mouse and human MII oocytes and embryos. All these transcripts and proteins play a role at the time of fertilization to direct the changes in remodeling of chromatin and maintenance of chromatin integrity and are also used in the zygote until the genome of embryo becomes active and  can transcribe its own repair genes of DNA. 


The several disorders that give rise to cancer, mainly cases including MMR, BER, or DSBR defects, include either idle base lesions or recombinogenic intermediates such as DSBs. The major aim of this article is to give attention to the inherent DNA protective mechanisms in these reproductive cells and discuss various genetic disorders which is linked to DNA repair defects and draw correlations between the nature of DNA damage and the pathological endpoints, such as cancer, neurological disease, and premature aging. 


Barbari, S. R., Kane, D. P., Moore, E. A., & Shcherbakova, P. V. (2018). Functional analysis of cancer-associated DNA polymerase ε variants in Saccharomyces cerevisiae. G3: Genes, Genomes, Genetics, 8(3), 1019-1029. 

Divakaruni, A. S., Wallace, M., Buren, C., Martyniuk, K., Andreyev, A. Y., Li, E., ... & Murphy, A. N. (2017). Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death. Journal of Cell Biology, 216(4), 1091-1105. 

Englund, M., Guermazi, A., Gale, D., Hunter, D. J., Aliabadi, P., Clancy, M., & Felson, D. T. (2008). Incidental meniscal findings on knee MRI in middle-aged and elderly persons. New England Journal of Medicine, 359(11), 1108-1115. 

García-Rodríguez, A., Gosálvez, J., Agarwal, A., Roy, R., & Johnston, S. (2019). DNA damage and repair in human reproductive cells. International Journal of Molecular Sciences, 20(1), 31 

Gavande, N. S., VanderVere-Carozza, P. S., Hinshaw, H. D., Jalal, S. I., Sears, C. R., Pawelczak, K. S., & Turchi, J. J. (2016). DNA repair targeted therapy: the past or future of cancer treatment?. Pharmacology & therapeutics, 160, 65-83. 

Gil, J., Ramsey, D., Pawlowski, P., Szmida, E., Leszczynski, P., Bebenek, M., & Sasiadek, M. M. (2018). The influence of tumor microenvironment on ATG4D gene expression in colorectal cancer patients. Medical Oncology, 35(12), 1-8. 

Gong, Y., Matthews, B., Cheung, D., Tam, T., Gadawski, I., Leung, D., ... & Sacks, S. (2002). Evidence of dual sites of action of dendrimers: SPL-2999 inhibits both virus entry and late stages of herpes simplex virus replication. Antiviral research, 55(2), 319-329. 

Kaur, G., Cholia, R. P., Mantha, A. K., & Kumar, R. (2014). DNA repair and redox activities and inhibitors of apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1): a comparative analysis and their scope and limitations toward anticancer drug development: Miniperspective. Journal of medicinal chemistry, 57(24), 10241-10256. 

Lokanga, R. A., Senejani, A. G., Sweasy, J. B., & Usdin, K. (2015). Heterozygosity for a hypomorphic Polβ mutation reduces the expansion frequency in a mouse model of the Fragile X-related disorders. PLoS Genet, 11(4), e1005181. 

Newton, K., Jorgensen, N. M., Wallace, A. J., Buchanan, D. D., Lalloo, F., McMahon, R. F. T., & Evans, D. G. (2014). Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC). Journal of medical genetics, 51(12), 789-796. 

Ryan, N. A., Morris, J., Green, K., Lalloo, F., Woodward, E. R., Hill, J., ... & Evans, D. G. (2017). Association of mismatch repair mutation with age at cancer onset in Lynch syndrome: implications for stratified surveillance strategies. JAMA oncology, 3(12), 1702-1706. 

Sawicka, B., Johar, S. K., Sood, P. P., & Gupta, P. D. (2017). Imbalance of gut microbiota induces cancer: a review. Journal of Cell & Tissue Research, 17(2). 

Scheibye-Knudsen, M., Mitchell, S. J., Fang, E. F., Iyama, T., Ward, T., Wang, J., & Bohr, V. A. (2014). A high-fat diet and NAD+ activate Sirt1 to rescue premature aging in cockayne syndrome. Cell metabolism, 20(5), 840-855. 


Stein, D. M., & Knight, W. A. (2017). Emergency neurological life support: traumatic spine injury. Neurocritical care, 27(1), 170-180. 

Tang, J. B., Goellner, E. M., Wang, X. H., Trivedi, R. N., St Croix, C. M., Jelezcova, E., & Sobol, R. W. (2010). Bioenergetic metabolites regulate base excision repair–dependent cell death in response to DNA damage. Molecular Cancer Research, 8(1), 67-79. 

Tiwari, V., & Wilson III, D. M. (2019). DNA damage and associated DNA repair defects in disease and premature aging. The American Journal of Human Genetics, 105(2), 237-257. 

Zeinalian, M., Hashemzadeh-Chaleshtori, M., Salehi, R., & Emami, M. H. (2018). Clinical aspects of microsatellite instability testing in colorectal cancer. Advanced biomedical research, 7. 

Author details

Jyotsna Setty1, Anjali2, Aakash3*, Bhanupriya Pankaj3 

1Ph.D. Scholar, Department of Plant Physiology, Institute of Agricultural Sciences, B.H.U, Varanasi-221005 (U.P.) 

2Ph.D. Scholar, Department of Plant Physiology, CBSH, GBPUA&T, Pantnagar, Uttarakhand-263145 (U.K.) 

3Ph.D. Scholar, Department of Agronomy, Institute of Agricultural Sciences, B.H.U, Varanasi-221005 (U.P.) 

*Corresponding Author - Aakash. E-mail:  aakashkushwah7004@gmail.com 

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