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Human survival demands genetic stability, therefore preventing changes to DNA is vital. However, DNA is often subject to damage caused by environmental chemicals and radiation, thermal accidents and relative molecules (Alberts et al. 2002). Ionising radiation and ultraviolet radiation are examples of environmental factors that lead to DNA damage and can result in approximately 100,000 DNA lesions per exposed cell per hour (Jackson and Bartek, 2009; Ciccia and Elledge, 2010). DNA lesions arise in cells via physiological processes such as single-stranded breaks, base modifications, base mismatch, incorporation of bulky adducts and abasic sites and double-stranded breaks (Jackson and Bartek, 2009; Bhattacharjee and Nandi, 2018). Damage to DNA can affect a cell’s ability to replicate and lead to mutations, having serious consequences on an organism’s viability (Alberts et al. 2002). Cells, therefore, require accurate mechanisms for both replicating their DNA and repairing any DNA errors.
DNA damage response
To maintain successful DNA, replicated DNA must be checked for damage, and repaired using a set of enzymes (Alberts et al. 2002). The DNA damage response (DDR) is a network of pathways involving DNA repair mechanisms and cell-cycle checkpoints. The type of response is dependent on the type of lesion present and is crucial for maintaining genome stability (Giglia-Mari, Zotter and Vermeulen, 2011; Bhattacharjee and Nandi, 2018).
DNA damage checkpoints
Several checkpoints are used to regulate the cell cycle. Damaged DNA is detected in the cycle and signals are generated by the damage to stop cell-cycle progression and increase DNA repair enzyme synthesis. ATM and ATR are protein kinases important for DDR-signalling. They are activated by double-strand breaks, which in turn initiate the activation of checkpoint proteins CHK1 and CHK2. These four proteins work together to reduce the activity of cyclin-dependent kinase (CDK), causing the cell cycle to slow down at specific checkpoints, therefore extending the time needed for DNA to repair before replication. Cells can then continue in the cell-cycle once DNA repair has been completed (Alberts et al. 2002; Hakem, 2008; Jackson and Bartek, 2009). Alternatively, if damaged DNA cannot be repaired, or if a cell has experienced too much damage, cell death is triggered by apoptosis. (Giglia-Mari, Zotter and Vermeulen, 2011).
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Defects in signalling proteins emphasise the importance of signalling mechanisms in the DNA damage response. Ataxia-telangiectasia (AT) is a rare, inherited disease caused by mutations in the gene that code for the ATM protein. The ATM protein is required for intracellular signals to be generated, needed to respond to certain types of DNA damage. Individuals with AT have a weakened immune system and lose their coordination of movement (Alberts et al. 2002; Bhattacharjee and Nandi, 2018).
DNA damage response pathways
Examples of DNA repair pathways include mismatch repair (MMR), nucleotide excision repair (NER), base excision repair (BER) pathway, homologous recombination (HR) pathway, and non-homologous end joining (NHEJ).
DNA mismatch repair pathways detect the insertion or deletion of nucleotides. Several proofreading mechanisms are used to prevent and correct any mispairing, involving the use of DNA polymerase, nuclease and ligase enzymes (Jackson and Bartek, 2009). For DNA polymerase to extend a nucleotide chain, it requires a base-paired 3-OH end of a primer strand. If mismatched nucleotides occur in a primer strand, it cannot act as templates for DNA polymerase to add further nucleotides. 3-to-5 proofreading exonuclease activity enables DNA polymerase to remove any mismatched and unpaired nucleotides in the primer terminus to allow DNA synthesis. Any non-complementary base-pairing missed by proofreading exonuclease is detected as a distortion in the DNA helix in strand-directed mismatch repair. The mismatched nucleotide where the replication error has occurred is identified and removed from the newly synthesised strand. To distinguish the new strand from the old strand to remove the correct mismatch, the newly synthesised DNA strand is known to be nicked. This is a single break that provides a signal to direct DNA mismatch repair to the correct strand. (Alberts et al. 2002). Mutations in genes involved in DNA mismatch repair, such as MLH1, MSH2 or MSH6, are associated with hereditary non-polyposis colorectal cancer (HNPCC). HNPCC is an inherited disease that results in the increased risk of cancers such as colorectal cancer and increased levels of microsatellite instability in the tumours (Hakem, 2008).
Base excision repair and nucleotide excision repair are pathways used to repair one damaged strand of a DNA double helix resulting from a single-strand break. Base excision repair involves DNA glcosylases enzymes that recognise chemically altered bases in DNA and removes them by processes such as alkylation, oxidation or deamination. (Giglia-Mari, Zotter and Vermeulen, 2011; Bhattacharjee and Nandi, 2018). The altered bases are identified by a mechanism called base flipping (Alberts et al. 2002). Alternatively, nucleotide excision repair recognises structural distortions in the double helix which are generated by bulky lesions and pyrimidine dimers, resulting from UV radiation. NER involves the action of approximately 25 polypeptides to remove and replace the damaged DNA region (Giglia-Mari, Zotter and Vermeulen, 2011; Bhattacharjee and Nandi, 2018).
Homologous recombination and non-homologous end-joining are the two pathways used to repair double-strand breaks. The homologous recombination pathway uses a homologous DNA template to transfer nucleotide sequences information across the double-strand break using general recombination mechanisms. This type of repair can take place between the two sister chromatids if DNA replication has yet to occur in cells. The use of DNA sequence homology means that HR is error-free. In contrast, non-homologous end-joining is an error-prone response whereby broken ends of the DNA strand are re-joined by DNA ligation. This mechanism does not require a homologous template to recover damaged DNA sequences at the site of the break (Alberts et al. 2002; Bhattacharjee and Nandi, 2018).
Diseases associated with defected DNA damage response
Genetic defects in known DNA damage response pathways can result in severe, rare human diseases, emphasising the importance of genome stability.
Congenital defects can occur in certain DNA glycosylases, leading to human disease. DNA glycosylases enzymes are important in base excision repair and are used to remove damaged or modified bases. Hyper-IgM syndrome (HIGM) is an example of a disease caused by defects in the enzymes uracil-DNA glycosylase (UNG) and activation-induced cytidine deaminase (AICDA). UNG is used to remove uracil from DNA and AICDA is needed for class switch recombination of Ig’s from IgM to other isotopes (O’Driscoll, 2012). HIGM individuals show immunodeficiency and high susceptibility to opportunistic infections (Montella et al. 2012). Xeroderma pigmentosum (XP) is a genetic disease resulting from a mutation of the nuclear excision repair genes XPA to XPG. XP is characterised by severe skin sensitivity to ultraviolet radiation and eye damage, both resulting from sun exposure. Individuals have a much greater risk of developing skin cancer as well as neurological abnormalities (Hakem, 2008). LIG4 syndrome and Art-severe Combined Immune Deficiency (SCID) are conditions caused by defects in DNA ligase IV (LIG4) and Artemis, important components needed for non-homologous end-joining. These conditions are linked to T-cell and B-cell deficiencies as NHEJ is used for the double-strand breaks repair in the immunoglobin and T-cell receptor genes, resulting in functional immunoglobins and T-cell receptors in the immune system. Patients with LIG4 syndrome and Art-SCID have a weakened immune system so they suffer from frequent infections (O’Driscoll, 2012). Fanconi anemia (FA) is a disorder characterised by bone marrow failure during childhood followed by the development of acute myeloid leukaemia and increased risk of developing tumours in adult life. FA can be caused by mutations in at least 21 genes that code for proteins involved in the DNA repair FA pathway, which has a functional connection to homologous recombination (O’Driscoll, 2012).
Therapies for DNA repair defects
Xeroderma pigmentosum is an example of a disease that has the potential to be treated by gene correction. This would be achieved by correcting XP-C cell defects, as defects lead to inactive NER protein expression, for example, the XPC gene. By engineering nucleases, strand breaks can be precisely initiated then repaired by homologous recombination using DNA repair matrix. For this correction to be successful, efficient nucleases must be generated. Gene therapy for XP would lead to the correct expression of the XPC protein and a functional NER pathway, therefore reducing the risk of skin cancer being developed by the individual. Gene correction in all skin cells would be required for efficient XP gene therapy, as DNA repair-deficient cells still have an increased risk of developing cancer. Currently, the XP phenotype has only been successfully corrected using viral vectors in vitro. (Menck et al.2007; Dupuy et al. 2013)
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Cancer is a disease that can be treated using defects DNA damage response pathways as an advantage. Chemotherapy and radiotherapy rely on abnormalities in DNA repair to work efficiently to induce DNA damage and kill cancer cells (Hosoya and Miyagawa, 2014). Both of these treatments are effective in slowing down the growth of cancer and reducing the risk of cancer returning, therefore benefiting the individual. However, these treatments can damage some healthy cells, as well as cancer cells therefore can cause side effects including hair loss, fatigue, and nausea. (Chemotherapy, no date).
Cells respond to all types of DNA damage in a variety of ways using many different DNA repair pathways and specific genes. Defects to these pathways or mutations in the genes involved are shown to lead to various health conditions including neurological degeneration, cancer susceptibility, and immune deficiency. These conditions emphasise how important it is for cells to have a functional DNA damage response network. At present, therapies are being trialled to repair inherited gene mutations for the treatment of these conditions. In addition to this, research into these defects is being done for a better understanding of the effects they have on human health.
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