New Potential Therapeutic Approaches by Targeting Rad51- Dependent Homologous Recombination

Abstract

Additional information is available at the end of the chapter http://dx.doi.org/10.5772/53973 . IntroductionCellular DNA is constantly exposed to the effects of endogenous or environmental agents such as free radicals, radiation and chemicals. In higher organisms, these nucleic alterations are estimated at several thousands of lesions per cell [ ] which can correspond to the loss of bases and also to the breaking of one or both strands of the DNA double helix. Among these DNA breaks, the double-strand break DSB is the most harmful because it is the most difficult to repair. A human cell can accumulate up to DSBs per cell cycle [ ]. Unrepaired DSBs can have serious consequences such as permanent cell cycle arrest or cell death by apoptosis. Imperfect repair can also lead to major syndromes such as genetic disorders, premature aging or malignant cell generation.In response to DNA damage, the cell has developed a surveillance and DNA repair network. DSBs of DNA, which are the most severe nucleic acid alterations, are repaired mainly by either non-homologous end-joining NHEJ or homologous recombination HR .NHEJ repair leads to a direct rejoining of the separated DNA ends [ ]. This pathway begins by the binding of the Ku / heterodimer to DNA ends Figure ] which recruits and induces the activation of the DNA-dependent protein kinase catalytic subunit DNA-PKc . Kinase activity is required for NHEJ since it causes the recruitment of other proteins and promotes the bringing together of DNA ends. Finally, ligase VI and XRCC /XLF co-factors are involved in the final step of ligation and the generation of DNA repair. This process involves mainly the G -G and S phases of the cell cycle. Its disadvantage is the possible loss of genetic information due to deletions or insertions of nucleic acids during the ligation of DNA ends and thus NHEJ repair is considered error-prone. DNA repair by HR is more complex and needs a homologous sequence, which can be present in the homologous chromosome or in a gene in multicopy [ ]. HR predominates in the S and G phases, when the sister chromatids are present and can also be a model for DNA repair [ ]. In eukaryotic cells, DNA repair is supported by several protein complexes. Protein ATM Ataxia Telangiectasia Mutated has a role in DSB signaling via its activation induced by the MRN protein complex MRE -Rad -NBS complex . MRE is a '-' exonuclease that leads to a ' end of DNA which is required for the process [ ]. This resection of single-stranded DNA is followed by the recruitment of many proteins such as RPA, BRCA , BRCA , Rad , Rad , and Rad . Rad is one of the first to settle on the DSB. BRCA then recruits BRCA , Rad and Rad to form the nucleoprotein filament with ssDNA, whose role is to move the blade to the homologous sequence required for HR. Rad protein is the main element involved in the HR process. This recombinase catalyzes the homology search and the strand exchange with a homologous sequence and thus ensures the accurate repair of the DSB. In eukaryotes, Rad recombinase RecA homol...

Targeting DNA Repair Pathways for Cancer Treatment: what’s new?

“…Post-translational modification of mediator proteins involved in HR repair highly regulate the balance of RPA and Rad51 so that repair is not inhibited and disassociation does not occur before Rad51's work is complete [72]. Rad51 overexpression is associated with breast and pancreatic cancers, non-small-cell lung cancer and leukemias [80]. …”

“…For example, mirin, which inhibits the MRE11–RAD50–NBS1 (MRN) complex (HR's damage sensor), also inhibits ATM and downregulates NHEJ [82]. With the exception of RI-1 (which has been tested in cell studies only) [82], small molecules that directly inhibit specific HR proteins are not in development (Table 6) [80,82–84]. …”

Identification and characterization of human Rad51 inhibitors by screening of an existing drug library

“…Given the involvement of Rad51 in such severe diseases, it represents an important target for anticancer therapy and the development of small molecule inhibitors capable of inhibiting Rad51 activities is warranted. Thence, very recently, few compounds have been identified as inhibitors of Rad51 and the great majority of them have been selected by high-throughput screening from chemical libraries [17][18][19][20]. However, the development of a new drug is a hard and expensive process, including the fact that new drugs have to undergo a challenging approval process by the Food and Drug Administration (FDA) in order to make sure that the drug is safe for consumption.…”

Development of Small Molecules that Specifically Inhibit the D-loop Activity of RAD51

“…[11][12][13] These observations support the concept of RAD51 as a therapeutic target and the development of small molecule therapeutics to sensitize tumors. [14][15][16] Although several small molecule RAD51 inhibitors have been developed, most of these inhibitors act by preventing the formation of RAD51-ssDNA nucleoprotein filaments. 13,14,[16][17][18][19] One possible exception is halenaquinone, a chemical purported to specifically inhibit D-loop formation by RAD51.…”

“…[14][15][16] Although several small molecule RAD51 inhibitors have been developed, most of these inhibitors act by preventing the formation of RAD51-ssDNA nucleoprotein filaments. 13,14,[16][17][18][19] One possible exception is halenaquinone, a chemical purported to specifically inhibit D-loop formation by RAD51. 20 However, halenaquinone also reduces the subnuclear appearance of RAD51 foci at DSB sites in cells, which raises questions as to its mechanistic interaction with RAD51 in cells.…”