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Biocatalysis contributes significantly to the development of more sustainable synthetic pathways by using mild reaction conditions and water as a solvent. However, many relevant classes of compounds, including privileged groups in drug design, are not yet accessible via enzymatic pathways. In this context, the development of an enzymatic route to indazoles remains an unmet challenge. Here, we present a nitroreductase-triggered indazole formation, in which 2-nitrobenzylamine derivatives are converted to reactive nitrosobenzylamine intermediates that spontaneously cyclize and aromatize to indazoles. Two nitroreductases accept a series of 2-nitrobenzylamine derivatives with excellent conversions (up to >99 %). In the case of N -substituted nitrosobenzylamines, 2 H -indazoles are formed, whereas other derivatives led to 1 H -indazoles. The synthetic value of the nitroreductase-triggered indazole formation is further demonstrated by successful coupling with an imine reductase in a sequential cascade reaction on a 50 mg scale. With this cascade, 2 H -indazoles are accessible from cheap 2-nitrobenzaldehyde and primary amines, resulting in up to 85 % conversion and 68 % isolated yield. An enzymatic route to indazoles, scaffolds present in many drugs, has not been developed yet. Here, the authors report nitroreductase-triggered indazole formation, in which 2-nitrobenzylamine derivatives are converted to reactive nitrosobenzylamine intermediates that spontaneously cyclize and aromatize to indazoles.

Many bioactive plant cyclic peptides form side-chain-derived macrocycles. Lyciumins, cyclic plant peptides with tryptophan macrocyclizations, are ribosomal peptides (RiPPs) originating from repetitive core peptide motifs in precursor peptides with plant-specific BURP (BNM2, USP, RD22 and PG1beta) domains, but the biosynthetic mechanism for their formation has remained unknown. Here, we characterize precursor-peptide BURP domains as copper-dependent autocatalytic peptide cyclases and use a combination of tandem mass spectrometry-based metabolomics and plant genomics to systematically discover five BURP-domain-derived plant RiPP classes, with mono- and bicyclic structures formed via tryptophans and tyrosines, from botanical collections. As BURP-domain cyclases are scaffold-generating enzymes in plant specialized metabolism that are physically connected to their substrates in the same polypeptide, we introduce a bioinformatic method to mine plant genomes for precursor-peptide-encoding genes by detection of repetitive substrate domains and known core peptide features. Our study sets the stage for chemical, biosynthetic and biological exploration of plant RiPP natural products from BURP-domain cyclases.BURP domains within lyciumin precursor peptides serve as autocatalytic peptide cyclases, enabling the discovery of other BURP-domain-derived products and development of a bioinformatic method to mine plants for precursor-peptide-encoding genes.

Faithful and timely repair of DNA double‐strand breaks (DSBs) is fundamental for the maintenance of genomic integrity. Here, we demonstrate that the meiotic recombination co‐factor MND1 facilitates the repair of DSBs in somatic cells. We show that MND1 localizes to DSBs, where it stimulates DNA repair through homologous recombination (HR). Importantly, MND1 is not involved in the response to replication‐associated DSBs, implying that it is dispensable for HR‐mediated repair of one‐ended DSBs. Instead, we find that MND1 specifically plays a role in the response to two‐ended DSBs that are induced by irradiation (IR) or various chemotherapeutic drugs. Surprisingly, we find that MND1 is specifically active in G2 phase, whereas it only marginally affects repair during S phase. MND1 localization to DSBs is dependent on resection of the DNA ends and seemingly occurs through direct binding of MND1 to RAD51‐coated ssDNA. Importantly, the lack of MND1‐driven HR repair directly potentiates the toxicity of IR‐induced damage, which could open new possibilities for therapeutic intervention, specifically in HR‐proficient tumors. Hypothetical model of the specific action of MND1/HOP2 complex on the repair of DSBs. We observe that the meiotic recombination co‐factor MND1 facilitates the repair of DSBs in somatic cells. Surprisingly, we find that MND1 is specifically active in G2 phase, whereas it only marginally affects repair during S phase.

The COVID-19 pandemic has resulted in over 340 million infection cases (as of 21 January 2022) and more than 5.57 million deaths globally. In reaction, science, technology and innovation communities across the globe have organised themselves to contribute to national responses to COVID-19 disease. A significant contribution has been from the establishment of wastewater-based epidemiological (WBE) surveillance interventions and programmes for monitoring the spread of COVID-19 in at least 55 countries. Here, we examine and share experiences and lessons learnt in establishing such surveillance programmes. We use case studies to highlight testing methods and logistics considerations associated in scaling the implementing of such programmes in South Africa, the Netherlands, Turkey and England. The four countries were selected to represent different regions of the world and the perspective based on the considerable progress made in establishing and implementing their national WBE programmes. The selected countries also represent different climatic zones, economies, and development stages, which influence the implementation of national programmes of this nature and magnitude. In addition, the four countries' programmes offer good experiences and lessons learnt since they are systematic, and cover extensive areas, disseminate knowledge locally and internationally and partnered with authorities (government). The programmes also strengthened working relations and partnerships between and among local and global organisations. This paper shares these experiences and lessons to encourage others in the water and public health sectors on the benefits and value of WBE in tackling SARS-CoV-2 and related future circumstances.

Faithful and timely repair of DNA double-strand breaks (DSBs) is fundamental for the maintenance of genomic integrity. Here, we demonstrate that the meiotic recombination co-factor MND1 facilitates the repair of DSBs in somatic cells. We show that MND1 localizes to DSBs, where it stimulates DNA repair through homologous recombination (HR). Importantly, MND1 is not involved in the response to replication-associated DSBs, implying that it is dispensable for HR-mediated repair of one-ended DSBs. Instead, we find that MND1 specifically plays a role in the response to two-ended DSBs that are induced by IR or various chemotherapeutic drugs, specifically in G2. MND1 localization to DSBs is dependent on resection of the DNA ends, and seemingly occurs through direct binding of MND1 to RAD51-coated ssDNA. Importantly, the lack of MND1-driven HR repair directly potentiates the toxicity of IR-induced damage, which could open new possibilities for therapeutic intervention, specifically in HR-proficient tumors.

Of all damage occurring to DNA, the double strand break (DSB) is the most toxic lesion. Luckily, cells have developed multiple repair pathways to cope with these lesions. These different pathways compete for the same break, and the location of the break can influence this competition. However, the exact contribution of break location in repair pathway preference is not fully understood. We observe that most breaks prefer classical non-homologous end-joining, whereas some depend on DNA end-resection for their repair. Surprisingly, we find that for a subset of these sites, the activation of resection-dependent repair induces a detrimental DNA damage response. These sites exhibit extensive DNA end-resection due to improper recruitment of 53BP1 and the Shieldin complex due to low levels of H4K20me2. Most of these sites reside in close proximity to DNAseI hypersensitive sites. Compacting or removing these regions reduces extensive DNA end-resection and restores normal repair. Taken together, we found that DSB in open chromatin is highly toxic, due to the improper activity of 53BP1 and Shieldin, resulting in extensive DNA end-resection.