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Ionizing radiation (IR), chemical carcinogens, and the ‘classic’ genotoxic anticancer drugs all attack the DNA, which is at the very heart of their genotoxic and toxic attributes. Therefore, it is important to shed light on the processes taking place on the level of damaged DNA, in order to facilitate our understanding of carcinogens and the effect of anticancer drugs on cells and tissues. Potentially lethal events for the cell are DNA double-strand breaks (DSBs) and DNA lesions that prevent the transcription and replication of DNA. Cells have developed sensors that detect these lesions. Sensor systems recognize the damage and relay the signal through kinases to ‘executors’, which start a process that either inhibits strengthens DNA repair and cell cycle progression or induces apoptosis that destroys the cell. The major ‘players’ of DNA damage recognition are ATM, ATR and DNA-PK, which phosphorylate a multitude of proteins and therefore induce the DNA damage response (DDR), in which p53 and BRCA1/2 play crucial roles. Downstream are targets that help cells to survive or destine them to undergo cell death.
Figure 1. Model for the DDR.
Generally speaking, the DDR can be divided into a series of distinct, but functionally interwoven, pathways, which are defined largely by the type of DNA lesion they process. Most DDR pathways contain a similar set of tightly coordinated processes: namely the detection of DNA damage, the accumulation of DNA repair factors at the site of damage and finally the physical repair of the lesion. Most of the subtle changes to DNA, such as alkylation products, oxidative lesions, and SSBs, are repaired via a series of mechanisms that is termed base excision repair (BER). In BER, damaged bases are first removed from the double helix, and then the ‘injured’ section of the DNA backbone is excised and replaced with newly synthesized DNA. Key to this process is the enzymes poly (ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2), which play as sensors and signal transducers for lesions. Apart from BER, the pool of deoxynucleotides that provide the building blocks of DNA can be chemically modified before they are incorporated into the double helix. Therefore, the nucleotide pool is continually ‘sanitized’ by enzymes such as nudix-type motif 5 (NUDT5).
Most carcinogens operate by generating DNA damage and causing mutations. In addition, inherited DDR defects commonly predispose to cancer, contribute to the ‘mutator phenotype’ of a number of malignancies, and may allow tumor-cell survival and proliferation despite enhanced mutation rates and genome instability. Especially, aberrant cell proliferation, caused by oncogene activation or inactivation of certain tumor suppressors, elicits DNA-replication stress and ongoing DNA-damage formation. Such damage activates ATR/ATM-mediated signaling, causing cell death or senescence in cell-culture models and during tumorigenesis in vivo. In fact, the DDR is commonly activated in early neoplastic lesions and probably protects against malignancy. It has been shown that breaches to this barrier, arising through mutational or epigenetic inactivation of DDR components, are subsequently selected for during tumor development, therefore allowing malignant progression. This model for the DDR as an anti-cancer barrier helps to explain the high frequency of DDR defects in human cancers.
DDR defects have already been exploited in the form of many commonly used chemotherapy and radiotherapy regimens. One example is the use of platinum salts frequently given in combination with the taxane paclitaxel in patients with advanced ovarian cancer. Platinum salts cause DNA inter- and intrastrand crosslinks — lesions that are recognized by the DDR and repaired by a combination of NER and homologous recombination. An alternative approach to chemotherapy is the design of drugs which target specific DDR components. Topoisomerase inhibitors could be regarded as the first generation of DDR ‘targeted’ agents. Topoisomerases catalyze the breaking and rejoining of the phosphodiester backbone as part of the process that unwinds the torsional structure of DNA before processes such as transcription and DNA replication; agents that inhibit this function leave DNA breaks across the genome and have been used effectively in some cancers. The development of the next generation of DDR inhibitors, particularly PARP inhibitors, has provided considerable impetus to this area.
The genomic instability of tumor cells is one of their most pervasive characteristics and presents a therapeutic opportunity. DNA-damaging chemotherapies have already provided the core of cancer treatment for the past half-century and, if used appropriately, targeted therapies that exploit the DDR could deliver better therapeutic responses in the future. Creative Biogene is able to offer various DNA damage pathway related products including stable cell lines, viral particles and clones for your drug discovery projects.
DNA Damage Pathway Product Panel
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