NAR’s Breakthrough Articles present high-impact studies answering long-standing questions in the field of nucleic acids research and/or opening up new areas and mechanistic hypotheses for investigation. These articles are chosen by the Editors on the recommendation of Editorial Board Members and Referees. Articles are accompanied by a brief synopsis explaining the findings of the paper and where they fit in the broader context of nucleic acids research. They represent the very best papers published at NAR.
Structure and mechanism of pyrimidine–pyrimidone (6-4) photoproduct recognition by the Rad4/XPC nucleotide excision repair complex
This study combines X-ray crystallographic structure determination with computational molecular dynamics simulations to determine a mechanism by which a DNA substrate containing a 6-4 photoproduct (6-4PP) lesion is recognized by a Rad4-Rad23 complex for its repair. This new structure shows how the 6-4PP is completely flipped out of the DNA double helix by Rad4. The authors then use MD simulations to show how the Rad4 initiates the displacement of 6-4PP by causing DNA untwisting, bending and base flipping. This is not the first structure determined of a Rad4-DNA complex; however, it is the first structure of Rad4 (or any XPC ortholog) bound to a bona fide lesion substrate that is recognizable in its natural DNA sequence context for nucleotide excision repair (NER) and provides structural evidence for mechanism of recognition and action that has been lacking.
Site-specific replacement of phosphorothioate with alkyl phosphonate linkages enhances the therapeutic profile of gapmer ASOs by modulating interactions with cellular proteins
This study describes a strategy to improve the therapeutic profile of antisense oligonucleotides (ASOs). ASOs are achieving clinical success, but some clinical trials continue to reveal toxicities that complicate use in patients. This paper reveals a relatively simple strategy for modifying ASOs to reduce unfavorable interactions with cellular proteins and thereby lessen the likelihood that major toxicities will be encountered in patients. By precisely tuning the chemical properties of ASOs, the authors reveal several case studies for improved activity. These results may lead to a new generation in ASOs that are similar in chemical make-up and biological activity to current ASOs but possess improved properties that will enhance their clinical value.
The nuclear structural protein NuMA is a negative regulator of 53BP1 in DNA double-strand break repair
It is essential for cell survival that DNA damage response proteins rapidly mobilize to DNA lesions. Importantly, these proteins must also be excluded from binding to undamaged chromatin. The mechanism of this exclusion is a long-standing question. This study by Vidi and coworkers demonstrates that DNA damage increases the diffusion speed of 53BP1, a key factor that binds to DNA double-strand breaks and regulates their repair. This increased diffusion speed results from reversal of sequestration by NuMA, a structural protein in the cell nucleus. This mechanism of reversible sequestration, which may extend to other DNA damage response and repair proteins, likely impacts the response to agents used in cancer treatment as well as physiological DNA repair in cells of the immune system. As predicted from the authors’ model, NuMA expression levels have prognostic value for breast cancer patients.