DNA Repair Mechanism

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1.5 DNA repair mechanism
DNA double strand breaks (DBSs) and single-strand breaks (SSBs) occur every day in cells and they are mostly caused by ionizing radiation, ultraviolet light, reactive oxygen species, errors during DNA replication, enzymes during meiosis. The repair of these DSBs and SSBs is essential to maintain genomic fidelity and stability. In order to combat DBSs and SSBs, cells have developed multiple distinct DNA repair mechanisms which detect damaged DNA, signal its presence and promote the repair of the damage (Jackson and Bartek, 2009). One of these mechanisms is base excision repair (BER). BER is a multi-step process that corrects non-bulky damage to bases resulting from oxidation, methylation, deamination, or spontaneous loss of the DNA base itself. In BER, DNA glycosylase recognises the damaged base and mediates base removal before proliferating cell nuclear antigen (PCNA), polymerase β and DNA ligase I or DNA Ligase III complete the repair process (Jackson and Bartek, 2009, David et al., 2007). Nucleotide excision repair (NER) is perhaps the most flexible of the DNA repair pathways. NER recognises and repairs lesions which are caused by helical distortion of the DNA duplex and pyrimidine dimers (cyclobutane pyrimidine dimers and 6-4 photoproducts) which are caused by the UV component of sunlight. Other NER substrates include bulky chemical adducts, DNA intrastrand crosslinks, and some forms of oxidative damage. Two distinct NER pathways exist: transcription-coupled NER which focuses on lesion blocking transcriptions and global genome NER which surveys the entire genome for distorting damage (Jackson and Bartek, 2009, David et al., 2007 ). DNA mismatch repair (MMR) pathway plays an essential role in the correc...

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...ing proteins. The large protein kinase, consisting of 4128 amino acids (aa), has a molecular weight of 469 kDA (33, 85-87). DNA-PKcs associates with the Ku70/80 heterodimer and forms a catalytic active DNA-PK holoenzyme (Falck et al., 2005). The kinase activity of DNA-PKcs is activated upon interaction with a free DNA. The protein can bind to DNA fragments in absence of the Ku complex. However its kinase activity appears to be much lower (Hammarsten and Chu, 1998). DNA-PKcs mediates the synapsis and ligation of the two DNA fragments (Block et al., 2004; Kysela et al., 2005). The auto-phosphorylation of DNA-PKcs results in the remodelling of DNA-Pk (Block et al., 2004). Moreover, DNA-PK phosphorylates the histons H2AX and H1.This might indicate that DNA-PK modifies chromatin structure to facilitate the access of other DNA repair complexes to DSBs (Kysela et al., 2005

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