Abstract
The DNA damage response enables cells to survive, maintain genome integrity, and to safeguard the transmission of high-fidelity genetic information. Upon sensing DNA damage, cells respond by activating this multifaceted DNA damage response leading to restoration of the cell, senescence, programmed cell death, or genomic instability if the cell survives without proper repair. However, unlike normal cells, cancer cells maintain a marked level of genomic instability. Because of this enhanced propensity to accumulate DNA damage, tumor cells rely on homologous recombination repair as a means of protection from the lethal effect of both spontaneous and therapy-induced double-strand breaks (DSBs) in DNA. Thus, modulation of DNA repair pathways have important consequences for genomic instability within tumor cell biology and viability maintenance under high genotoxic stress. Efforts are underway to manipulate specific components of the DNA damage response in order to selectively induce tumor cell death by augmenting genomic instability past a viable threshold. New evidence suggests that RAD52, a component of the homologous recombination pathway, is important for the maintenance of tumor genome integrity. This review highlights recent reports indicating that reducing homologous recombination through inhibition of RAD52 may represent an important focus for cancer therapy and the specific efforts that are already demonstrating potential.
Highlights
DNA damage is a normal occurrence, with the average cell facing up to one million DNA damaging events each day [1]
By eliminating key elements in the DNA damage response, provocation of synthetic lethality or sensitization of otherwise-resistant tumor cells may be possible through generation of an overwhelming level of spontaneous and lethal DNA damage
Unlike previous data showing that knockout models of Rad51 are lethal to normal cells both in vivo and in vitro, this precise method solely effects tumor cells and does not cause damage to normal cells because recombinational repair is mostly active in S-phase of the cell cycle where DNA is being replicated at a high rate in ultra-proliferative tumor cells [75, 76]
Summary
DNA damage is a normal occurrence, with the average cell facing up to one million DNA damaging events each day [1]. Despite its similarities to the renowned breast cancer tumor suppressor and its hypothesized purpose of repairing damaged DNA in order to maintain viability in normal cells, differential expression of the RAD52 gene has been shown to function in the progression of tumorigenesis both on its own accord, as well as in the absence of BRCA proteins [27, 29,30,31,32,33,34].
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