Transcriptional dysregulation is a hallmark of cancer and can be an essential driver of cancer initiation and progression. Loss of transcriptional control can cause cancer cells to become dependent on certain regulators of gene expression. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate the expression of multiple genes involved in carcinogenesis. BET inhibitors (BETis) disrupt BET protein binding to acetylated lysine residues of chromatin and suppress the transcription of various genes, including oncogenic transcription factors. Phase I and II clinical trials demonstrated BETis’ potential as anticancer drugs against solid tumours and haematological malignancies; however, their clinical success was limited as monotherapies. Emerging treatment-associated toxicities, drug resistance and a lack of predictive biomarkers limited BETis’ clinical progress. The preclinical evaluation demonstrated that BETis synergised with different classes of compounds, including DNA repair inhibitors, thus supporting further clinical development of BETis. The combination of BET and PARP inhibitors triggered synthetic lethality in cells with proficient homologous recombination. Mechanistic studies revealed that BETis targeted multiple essential homologous recombination pathway proteins, including RAD51, BRCA1 and CtIP. The exact mechanism of BETis’ anticancer action remains poorly understood; nevertheless, these agents provide a novel approach to epigenome and transcriptome anticancer therapy.

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The development of conventional, silicon-based computers has several limitations, including some related to the Heisenberg uncertainty principle and the von Neumann “bottleneck”. Biomolecular computers based on DNA and proteins are largely free of these disadvantages and, along with quantum computers, are reasonable alternatives to their conventional counterparts in some applications. The idea of a DNA computer proposed by Ehud Shapiro’s group at the Weizmann Institute of Science was developed using one restriction enzyme as hardware and DNA fragments (the transition molecules) as software and input/output signals. This computer represented a two-state two-symbol finite automaton that was subsequently extended by using two restriction enzymes. In this paper, we propose the idea of a multistate biomolecular computer with multiple commercially available restriction enzymes as hardware. Additionally, an algorithmic method for the construction of transition molecules in the DNA computer based on the use of multiple restriction enzymes is presented. We use this method to construct multistate, biomolecular, nondeterministic finite automata with four commercially available restriction enzymes as hardware. We also describe an experimental applicaton of this theoretical model to a biomolecular finite automaton made of four endonucleases.

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Rheumatoid arthritis (RA) is a systemic, inflammatory disease of the joints and surrounding tissues. RA manifests itself with severe joint pain, articular inflammation, and oxidative stress. RA is associated with certain types of cancer. We have assumed that RA patients’ increased susceptibility to cancer may be linked with genomic instability induced by impaired DNA repair and sensitivity to DNA damaging agents. The aim of this work was to analyze the sensitivity of peripheral blood mononuclear cells (PBMCs) isolated from RA patients to DNA damaging agents: tert-butyl hydroperoxide (TBH), bleomycin, ultraviolet (UV) radiation, and methyl methanesulfonate (MMS) and calculate the repair efficiency. TBH induce oxidative DNA lesions repaired mainly by base excision repair (BER). Bleomycin induced mainly DNA double-strand breaks repaired by non-homologous end joining (NHEJ) and homologous recombination repair (HRR). We included 20 rheumatoid arthritis patients and 20 healthy controls and used an alkaline version of the comet assay with modification to measure sensitivity to DNA damaging agents and DNA repair efficiency. We found an increased number of DNA breaks and alkali-labile sites in the RA patients compared to those in the controls. Exposure to DNA damaging agents evoked the same increased damage in both groups, but we observed statistically higher PMBC sensitivity to TBH, MMS, bleomycin as well as UV. Examination of the repair kinetics of both groups revealed that the DNA lesions induced by TBH and bleomycin were more efficiently repaired in the controls than in the patients. These data suggest impaired DNA repair in RA patients, which may accelerate PBMC aging and/or lead to higher cancer incidence among RA patients.

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