Radiation therapy plays an important role in the management of a wide range of cancers. Besides innovations in the physical application of radiation dose, radiation therapy is likely to benefit from novel approaches exploiting differences in radiation response between normal and tumor cells. While ionizing radiation (IR)* induces a variety of DNA lesions, including base damages and single-strand breaks (SSBs), the DNA double-strand break (DSB) is widely considered as the lesion responsible not only for the aimed cell killing of tumor cells, but also for the general genomic instability that leads to the development of secondary cancers among normal cells. Homologous recombination repair (HRR), non-homologous end-joining (NHEJ) and alternative NHEJ, operating as a backup, are the major pathways utilized by cells for the processing of DSBs. Therefore, their function represents a major mechanism of radiation resistance in tumor cells. HRR is also required to overcome replication stress - a potent contributor to genomic instability that fuels cancer development. HRR and alternative NHEJ show strong cell cycle dependency and are likely to benefit from radiation therapy mediated redistribution of tumor cells throughout the cell cycle. Moreover, the synthetic lethality phenotype documented between HRR deficiency and PARP inhibition has opened new avenues for targeted therapies. These observations make HRR a particularly intriguing target for treatments aiming to improve the efficacy of radiation therapy. Here, we briefly describe the major pathways of DSB repair and review their possible contribution to cancer cell radioresistance. Finally, we discuss promising alternatives for targeting DSB repair to improve radiation therapy and cancer treatment.

Manganese is an essential trace element; nevertheless, on conditions of overload, it becomes toxic, with neurotoxicity being the main concern. Chromate is a well-known human carcinogen. The underlying mechanisms seem to be oxidative stress as well as direct DNA damage in the case of chromate, but also interactions with DNA repair systems in both cases. However, the impact of manganese and chromate on DNA double-strand break (DSB) repair pathways is largely unknown. In the present study, we examined the induction of DSB as well as the effect on specific DNA DSB repair mechanisms, namely homologous recombination (HR), non-homologous end joining (NHEJ), single strand annealing (SSA), and microhomology-mediated end joining (MMEJ). We applied DSB repair pathway-specific reporter cell lines, pulsed field gel electrophoresis as well as gene expression analysis, and investigated the binding of specific DNA repair proteins via immunoflourescence. While manganese did not seem to induce DNA DSB and had no impact on NHEJ and MMEJ, HR and SSA were inhibited. In the case of chromate, the induction of DSB was further supported. Regarding DSB repair, no inhibition was seen in the case of NHEJ and SSA, but HR was diminished and MMEJ was activated in a pronounced manner. The results indicate a specific inhibition of error-free HR by manganese and chromate, with a shift towards error-prone DSB repair mechanisms in both cases. These observations suggest the induction of genomic instability and may explain the microsatellite instability involved in chromate-induced carcinogenicity.

Here, the complete assembly of the Moritella marina MP-1 (ATCC 15381) genome, combining Illumina and long Nanopore reads, is presented. The gapless assembly consists of a 4.7-Mb circular chromosome and a 26-kb plasmid, with a G+C content of 40.7%, and will assist in further studies of the molecular pathways in this biotechnologically significant organism.

Listeria monocytogenes is a major foodborne pathogen, responsible for severe listeriosis outbreaks associated with contaminated foods. This study reports the comparative genomic analysis of three novel L. monocytogenes strains C5, A2D9 and A2D10, obtained from dairy and clinical sources. Hybrid genome sequencing with Oxford-Nanopore and Illumina technologies provided high-quality complete chromosomes. Phylogenomic analysis revealed a highly conserved core genome alongside accessory genome diversity. Strain C5 belonged to sequence type ST2, while A2D9 and A2D10 were assigned to ST155 and ST1, respectively. All strains exhibited close genomic relatedness to isolates from dairy animals and/or the dairy environment. Functional analysis identified conserved metabolic functions across all genomes. A total of 40 virulence genes were detected, including the LIPI-1 island in all strains and the LIPI-3 operon exclusively in A2D10, indicating a potential hypervirulent phenotype consistent with its ST1 background and the associated fatal clinical outcome. All strains exhibited similar antimicrobial resistance profiles typical of L. monocytogenes and diverse defense systems. The newly sequenced strains provide a valuable resource for functional analyses of the mechanisms underlying adaptation of L. monocytogenes to diverse environments.