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

Homologous Recombination (HR) plays an essential role in cellular proliferation and in maintaining genomic stability by repairing DNA double-stranded breaks that appear during replication. Rad51, a key protein of HR in eukaryotes, can have an elevated expression level in tumor cells, which correlates with their resistance to anticancer therapies. Therefore, targeted inhibition of Rad51 through inhibitor may improve the tumor response to these therapies. In order to identify small molecules that inhibit Rad51 activity, we screened the Prestwick Library (1120 molecules) for their effect on the strand exchange reaction catalyzed by Rad51. We found that Chicago Sky Blue (CSB) is a potent inhibitor of Rad51, showing IC₅₀ values in the low nanomolar range (400 nM). Biochemical analysis demonstrated that the inhibitory mechanism probably occurs by disrupting the Rad51 association with the single-stranded DNA, which prevents the nucleoprotein filament formation, the first step of the protein activity. Structure Activity Relationship analysis with a number of compounds that shared structure homology with CSB was also performed. The sensitivity of Rad51 inhibition to CSB modifications suggests specific interactions between the molecule and Rad51 nucleofilament. CSB and some of its analogs open up new perspectives in the search for agents capable of potentiating chemo- and radio-therapy treatments for cancer. Moreover, these compounds may be excellent tools to analyze Rad51 cellular functions. Our study also highlights how CSB and its analogs, which are frequently used in colorants, stains and markers, could be responsible of unwanted side effects by perturbing the DNA repair process.     

Central sleep apnea: Pathophysiology and treatment

Central sleep apnea (CSA) is characterized by a lack of drive to breathe during sleep, resulting in repetitive periods of insufficient ventilation and compromised gas exchange. These nighttime breathing disturbances can lead to important comorbidity and increased risk of adverse cardiovascular outcomes. There are several manifestations of CSA, including high altitude-induced periodic breathing, idiopathic CSA, narcotic-induced central apnea, obesity hypoventilation syndrome, and Cheyne-Stokes breathing. While unstable ventilatory control during sleep is the hallmark of CSA, the pathophysiology and the prevalence of the various forms of CSA vary greatly. This brief review summarizes the underlying physiology and modulating components influencing ventilatory control in CSA, describes the etiology of each of the various forms of CSA, and examines the key factors that may exacerbate apnea severity. The clinical implications of improved CSA pathophysiology knowledge and the potential for novel therapeutic treatment approaches are also discussed.     

Role of DNA Repair-related Gene Polymorphisms in Susceptibility to Risk of Prostate Cancer

Aim: We assessed the association between genetic variants of XPG, XPA, XPD, CSB, XPC and CCNH inthe nucleotide excision repair (NER) pathway and risk of prostate cancer. Methods: We genotyped the XPG,XPA, XPD, CSB, XPC and CCNH polymorphisms by a 384-well plate format on the MassARRAY® platform.Multivariate logistical regression analysis was used to assess the associations between the six gene polymorphismsand risk of prostate cancer. Results: Individuals carrying the XPG rs229614 TT (OR=2.01, 95%CI=1.35-3.27)genotype and T allele (OR=1.73, 95%CI=1.37-2.57) were moderately significantly associated with a higher riskof prostate cancer. Subjects with XPD rs13181 G allele had a marginally increased risk of prostate cancer, withadjusted OR(95%CI) of 1.53 (1.04-2.37). Moreover, individuals carrying with CSB rs2228526 GG genotype(OR=2.05, 95% CI=1.23-3.52) and G allele (OR=1.56, 95%CI=1.17-2.05) were associated with a higher increasedrisk of prostate cancer. The combination genotype of XPG rs2296147 T and CSB rs2228526 G allele hadaccumulative effect on the risk of this cancer, with an OR (95% CI) of 2.23(1.37-3.59). Conclusions: Our studyindicates that XPG rs2296147 and CSB rs2228526 polymorphisms are significantly associated with increasedrisk of prostate cancer, and that combination of XPG rs2296147 T allele and CSB rs2228526 G allele is stronglyassociated with an increased risk.