Single base substitution signatures 17a, 17b, and 40 are induced by γ-ray irradiation in association with increased reactive oxidative species.

γ-Ray irradiation induces DNA double strand breaks (DSBs) and increases the risk of cancerization. Irradiated cells usually repair DSBs directly, but accumulate replication stress-associated DSBs, increasing the risk of structural variants (SVs). Although single nucleotide variants (SNVs) are also induced, it is still unclear which SNVs are induced by γ-ray irradiation. Here, we show that single base substitution (SBS) 17a, 17b, and 40 signatures were induced by γ-ray irradiation, which is mainly SNV induction in A-T bps. While SNVs induced by genomic instability were usually associated with SVs, SNVs induced by γ-ray irradiation and the associated signatures were not. As reactive oxygen species (ROS) are a possible cause of SBS17a and 17b, ROS were induced upon γ-ray irradiation (1-8 Gy), indicating the association of ROS for the SNV induction. Thus, our results reveal that ROS-associated SNVs are increased by irradiation, and that ROS-associated SNVs are induced independently of SVs.

Genome destabilization-associated phenotypes arising as a consequence of therapeutic treatment are suppressed by Olaparib.

Malignancy is often associated with therapeutic resistance and metastasis, usually arising after therapeutic treatment. These include radio- and chemo-therapies, which cause cancer cell death by inducing DNA double strand breaks (DSBs). However, it is still unclear how resistance to these DSBs is induced and whether it can be suppressed. Here, we show that DSBs induced by camptothecin (CPT) and radiation jeopardize genome stability in surviving cancer cells, ultimately leading to the development of resistance. Further, we show that cytosolic DNA, accumulating as a consequence of genomic destabilization, leads to increased cGAS/STING-pathway activation and, ultimately, increased cell migration, a precursor of metastasis. Interestingly, these genomic destabilization-associated phenotypes were suppressed by the PARP inhibitor Olaparib. Recognition of DSBs by Rad51 and genomic destabilization were largely reduced by Olaparib, while the DNA damage response and cancer cell death were effectively increased. Thus, Olaparib decreases the risk of therapeutic resistance and cell migration of cells that survive radio- and CPT-treatments.

Echoed induction of nucleotide variants and chromosomal structural variants in cancer cells.

Generally, the number of single-nucleotide variants (SNVs) in somatic cells increases with age, which is expected for replication errors. The number of SNVs in cancer cells, however, is often much higher than that in somatic cells, raising the question of whether cancer cells possess SNV induction pathways. The present study shows that the number of SNVs in cancer cells correlates with the number of chromosomal structural variants (SVs). While Kataegis, localized hypermutations typically arising near SV sites, revealed multiple SNVs within 1 kb, SV-associated SNVs were generally observed within 0.1-1 Mb of SV sites, irrespective of Kataegis status. SNVs enriched within 1 Mb of SV regions were associated with deficiency of DNA damage repair, including HR deficiency-associated single base substitution 3 (SBS3) and exogenous damage-associated SBS7 and SBS36 signatures. We also observed a similar correlation between SVs and SNVs in cells that had undergone clonal evolution in association with genomic instability, implying an association between genomic instability and SV-associated induction of SNVs.