TopBP1 in DNA Damage Response

Abstract

DNA, the genetic material of cells, is constantly exposed to a range of endogenous and environmental damaging agents (Jungmichel & Stucki, 2010). DNA molecule is the target of endogenous cellular metabolites such as reactive oxygen species (ROS) (Ciccia & Elledge, 2010; Poehlmann & Roessner, 2010). ROS may cause different alterations in a genome, e.g. simple DNA mutations, DNA single and double strand breaks (SSBs and DSBs, respectively), or more complex changes, including deletions, translocations and fusions (Poehlmann & Roessner, 2010). Alterations may be generated spontaneously due to dNTP misincorporation during DNA replication, interconversion between DNA bases caused by deamination, loss of DNA bases following DNA depurination or depyrimidination and modification of DNA bases by alkylation. Hydrolytic deamination (loss of an amino group) can directly convert one base to another. For example, deamination of cytosine results in uracil and with much lower frequency converts adenine to hypoxanthine. In depurination or depyrimidination, purine or pyrimidine bases are completely removed, leaving deoxyribose sugar depurinated or depyrimidinated that may cause breakage in the DNA backbone (Ciccia & Elledge, 2010; Rastogi et al., 2010). Altogether, it has been estimated that every cell could experience up to 105 spontaneous DNA lesions per day (Ciccia & Elledge, 2010). Environmental DNA damage can be produced by physical or chemical sources, such as ionizing radiation (IR), ultraviolet (UV) light from sunlight and organic and inorganic chemical substances (Muniandy et al., 2010; Rastogi et al., 2010; Su et al., 2010). Exposure to ionizing radiation from, e.g. cosmic radiation and medical treatments employing X-rays or radiotherapy inflicts DNA single and double strand breaks, oxidation of DNA bases and DNA-protein crosslinks in the genomic DNA (Ciccia & Elledge, 2010; Su et al., 2010). Ionizing radiation provokes DNA damage directly by energy deposit on the DNA double helix and indirectly by reactive oxygen/nitrogen species (ROS/RNS) (Corre et al., 2010). Ultraviolet radiation (mainly UV-B) is a powerful agent that may lead to the formation of three major classes of DNA lesions, such as cyclobutane pyrimidine dimmers (CPDs), pyrimidine 6-4 pyrimidone photoproducts (6-4 PPs) and their Devar isomers (Rastogi et al., 2010). Cells may become transiently exposed to external sources of DNA damage, such as cigarette smoke or various toxic chemical compounds (Jungmichel & Stucki, 2010). Many antineoplastic drugs currently used in cancer treatment express their cytotoxic effects through their ability to directly or indirectly damage DNA and thus resulting in cell death. Major types of DNA damage induced by anticancer treatment include single and double strand breaks, interstrand, intrastrand and DNA-protein crosslinks, as well as interference