To achieve this, oncogenes increase DNA replication origin firing leading to replication stress due to altered nucleotide levels and replication fork speed. In addition, tumorigenesis requires the activation of oncogenes, which in turn stimulate the uncontrolled proliferation of the cells. O 2 −) are extremely reactive particles capable of damaging molecules in their immediate vicinity, including DNA, creating a significant DSB burden if their production is left unattended.Oxygen-containing radicals such as hydroxyl radicals ( It has been shown that ROS generated during oxidative metabolism are among the primary sources of double-strand DNA breaks in eukaryotic cells. Taking into account the huge number of mutations arising constantly and their potential to inflict detrimental effects, it is logical that for billions of years of evolution, cells have been developing mechanisms for the detection and repair of DNA lesions. It has been estimated that every nucleated cell in the human body suffers approximately 70,000 DNA lesions every day, and external sources of mutation only increase this number. Accumulation of DNA lesions has been implicated in cell cycle arrest, cell senescence and death, aging, tumorigenesis, diverse developmental defects, and neurodegenerative diseases. However, on the other hand, most mutations are deleterious and disrupt the function(s) of the damaged genes, leading to various pathologies. On the one hand, the emergence of mutations in DNA, which generate new alleles or change the position or the number of the genes in the genome, is the driving force of evolution since these mutations are the “raw material” upon which evolution exerts selection. However, it did not take much time before scientists discovered that DNA is subject to the damaging effects of multiple mutagens that generate a remarkable diversity of harmful lesions. Following the discovery of its notable double helical structure, DNA was considered a fairly stable molecule. Given the paramount importance of DSB repair in tumorigenesis and cancer progression, DSB repair has turned into an attractive target for the development of novel anticancer therapies, some of which have already entered the clinic.ĭNA carries all hereditary genetic instructions dictating and regulating cellular functions and fate. Dynamic chromatin changes ensure accessibility to the damaged region, recruit DNA repair proteins, and regulate their association and activity, contributing to DSB repair pathway choice and coordination. Chromatin alterations, such as changing patterns of histone modifications shaped by numerous histone-modifying enzymes and chromatin remodeling, are pivotal for proficient DSB repair. The chromatin is not just a passive background that accommodates the multitude of DNA repair proteins, but it is a highly dynamic and active participant in the repair process. In eukaryotic cells, DSB repair is fulfilled in the immensely complex environment of the chromatin. Not surprisingly, cells have evolved several DSB repair pathways encompassing hundreds of different DNA repair proteins to cope with this challenge. They sever both DNA strands and compromise genomic stability, causing deleterious chromosomal aberrations that are implicated in numerous maladies, including cancer. Probably the most severe type of insults DNA could suffer are the double-strand DNA breaks (DSBs). Cellular DNA is constantly being damaged by numerous internal and external mutagenic factors.
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