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Summary: Translesion DNA synthesis (TLS) facilitates replication over damaged or difficult-to-replicate templates by employing specialized DNA polymerases. We investigate the effect on spontaneous mutagenesis of three main TLS control mechanisms: REV1 and PCNA ubiquitylation that recruit TLS polymerases and PRIMPOL that creates post-replicative gaps. Using whole-genome sequencing of cultured human RPE-1 cell clones, we find that REV1 and Polymerase ζ are wholly responsible for one component of base substitution mutagenesis that resembles homologous recombination deficiency, whereas the remaining component that approximates oxidative mutagenesis is reduced in PRIMPOL−/− cells. Small deletions in short repeats appear in REV1−/− PCNAK164R/K164R double mutants, revealing an alternative TLS mechanism. Also, 500–5,000 bp deletions appear in REV1−/− and REV3L−/− mutants, and chromosomal instability is detectable in REV1−/− PRIMPOL−/− cells. Our results indicate that TLS protects the genome from deletions and large rearrangements at the expense of being responsible for the majority of spontaneous base substitutions.

Loss of BRCA1 or BRCA2 results in genomic instability; however most studies have focused on the role of these proteins in double-strand break repair. Here the authors coupled cell line genetics and whole genome sequencing to investigate the formation of base substitutions and short indels in BRCA1-deficient cells, revealing a role for translesion DNA synthesis regulated by 53BP1.

The term called Industry 4.0 (I4.0) is an umbrella-concept, which encompasses several elements from the latest technological trends influencing the human workforce and education. But the questions arise: Does the industry 4.0 concept itself change workforce competencies? What is the impact on education? Thus far, only the technological aspects have been investigated thoroughly, despite their well-known, and strong, influence on the economy and society. This study addresses the interactions, dependencies, and correlations between certain areas of social existence, as expectations change regarding human competencies and their continued role in economic sectors and technological innovation. The role of the human factor within society is unquestionable as we start to understand why industrial revolutions have appeared. Fundamentally, it is always human concerns that stimulate change and it is human/social aspects that are heavily influenced by the same changes. As the I4.0 concept has an influence not just on how products are manufactured but also on the practices of consuming “products”, governments, research institutes, education systems, and organisations all have a crucial role to play in managing the massive wave of change. We believe that the concept should be more deeply analysed and understood, as it might give rise to a new complex terminology for techno-social change, which eventually would feed into achieving economic goals more efficiently.

Summary: Mutational signatures defined by single base substitution (SBS) patterns in cancer have elucidated potential mutagenic processes that contribute to malignancy. Two prevalent mutational patterns in human cancers are attributed to the APOBEC3 cytidine deaminase enzymes. Among the seven human APOBEC3 proteins, APOBEC3A is a potent deaminase and proposed driver of cancer mutagenesis. In this study, we prospectively examine genome-wide aberrations by expressing human APOBEC3A in avian DT40 cells. From whole-genome sequencing, we detect hundreds to thousands of base substitutions per genome. The APOBEC3A signature includes widespread cytidine mutations and a unique insertion-deletion (indel) signature consisting largely of cytidine deletions. This multi-dimensional APOBEC3A signature is prevalent in human cancer genomes. Our data further reveal replication-associated mutations, the rate of stem-loop and clustered mutations, and deamination of methylated cytidines. This comprehensive signature of APOBEC3A mutagenesis is a tool for future studies and a potential biomarker for APOBEC3 activity in cancer.

Abstract Background Homologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction. Results Using whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity. Conclusion Our results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity.

Metabolic syndrome is one of the most frequent diseases of our age, and it is accompanied by numerous complications. Clinical studies have been published suggesting that, in addition to the already well-known consequences of the metabolic syndrome, hepatic involvement should also be taken into consideration in a significant part of cases. Fatty liver or in most cases the histological picture of non-alcoholic steatohepatitis can mainly be observed in metabolic syndrome. These conditions may develop into hepatic cirrhosis, hepatic failure, or even hepatocellular cancer. The more components of the metabolic syndrome are present, and the more severe they are, the higher the likelihood of this transition is to happen. All these facts underscore the importance of assessing the hepatological status in patients with the metabolic syndrome.