ABSTRACT
Upon any DNA damage, the cell activates specific cellular DNA repair pathways for the correct repair of specific DNA lesions. Endogenous damage arises from DNA replication as replication forks stall or collapse or from ROS-generating toxic metabolic intermediates. Different DNA repair pathways such as homologous recombination (HR) or translesion synthesis (TLS) occur at replication forks to ensure proper replication, preventing genomic instability. Transcription-coupled repair (TCR), as the name implies, is a DNA repair mechanism that works in tandem with transcription. The stalling of RNA polymerase by DNA lesions activates TCR, which involves various repair proteins such as XPG, CSB, and TFIIH. Some of these DNA lesions may occur endogenously, for example, as a result
of misincorporation of nucleotides or DNA replication slippage, which leads to insertions or deletions. Exogenous DNA damage, in the form of environmental toxins, chemicals, radiation, or materials, may also result in these replication errors. • Oxidative stress. The by-products of many metabolic and biological reactions also result in the formation of ROS. These ROS include superoxide (O2-·), hydrogen peroxide (H2O2), hydroxyl radicals (OH·), and singlet oxygen (1O2), which can oxidize DNA and lead to several types of DNA damage, including oxidized bases and single-and double-
strand breaks (DSBs). Among the oxidatively modified bases, 8-hydroxy-2-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) is the most abundant base lesion. It base pairs preferentially with adenine rather than cytosine, resulting in GCÆTA transversion mutations after DNA replication. ROS can also increase the cleavage of the glycosidic bond between the bases and deoxyribose in DNA, generating abasic (AP) sites. AP sites are one of the most frequent endogenous DNA lesions in the cell with an estimated 10,000 lesions/human cell/day. DNA bases are also susceptible to hydrolytic deamination. Cytosine and 5-methylcytosine are frequently deaminated to uracil. The deaminated form is then rapidly excised by the DNA repair protein uracil-DNA glycosylase, which functions in the base excision repair (BER) pathway, resulting in abasic sites. AP sites are mutagenic due to the preferential incorporation of adenine opposite the abasic sites by DNA polymerases. In some cases, frame-shift deletions may occur at AP sites, contributing to further genomic instability [3, 4]. • Lipid peroxidation. The polyunsaturated fatty acids of phospholipids are highly sensitive to oxidation. The initial products of unsaturated fatty acid oxidation are reduced by glutathione peroxidases to unreactive fatty acid alcohols or aldehydes such as crotonaldehyde, acrolein, 4-hydroxynonenal, and malondialdehyde. The end products may lead to carcinogenesis. For example, malondialdehyde reacts with deoxyadenosine and deoxyguanosine in DNA, forming DNA adducts and interstrand crosslinks.
