Human DNA topoisomerase I poisoning causes R loop-mediated genome instability attenuated by transcription factor IIS.

DNA topoisomerase I can contribute to cancer genome instability. During catalytic activity, topoisomerase I forms a transient intermediate, topoisomerase I-DNA cleavage complex (Top1cc) to allow strand rotation and duplex relaxation, which can lead to elevated levels of DNA-RNA hybrids and micronuclei. To comprehend the underlying mechanisms, we have integrated genomic data of Top1cc-triggered hybrids and DNA double-strand breaks (DSBs) shortly after Top1cc induction, revealing that Top1ccs increase hybrid levels with different mechanisms.

Non-B DNA structures as a booster of genome instability.

Non-canonical secondary structures (NCSs) are alternative nucleic acid structures that differ from the canonical B-DNA conformation. NCSs often occur in repetitive DNA sequences and can adopt different conformations depending on the sequence. The majority of these structures form in the context of physiological processes, such as transcription-associated R-loops, G4s, as well as hairpins and slipped-strand DNA, whose formation can be dependent on DNA replication.

G-quadruplex binders as cytostatic modulators of innate immune genes in cancer cells.

G-quadruplexes (G4s) are non-canonical nucleic acid structures involved in fundamental biological processes. As G4s are promising anticancer targets, in past decades the search for effective anticancer G4 binders aimed at the discovery of more cytotoxic ligands interfering with specific G4 structures at oncogenes or telomeres. Here, we have instead observed a significant activation of innate immune genes by two unrelated ligands at non-cytotoxic concentrations.

An increased burden of rare exonic variants in NRXN1 microdeletion carriers is likely to enhance the penetrance for autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by a complex polygenic background, but with the unique feature of a subset of cases (~15%-30%) presenting a rare large-effect variant. However, clinical interpretation in these cases is often complicated by incomplete penetrance, variable expressivity and different neurodevelopmental trajectories. NRXN1 intragenic deletions represent the prototype of such ASD-associated susceptibility variants.