Non-homologous-end joining articles from across Nature Portfolio

Cryo-EM structures of human DNA-dependent protein kinase in intermediate and active states reveal the molecular mechanism of the allosteric activation of the atypical kinase complex, explaining why it is DNA dependent.

Chandramouly et al. discover that human Polλ exhibits robust microhomology-mediated end-joining (MMEJ) activity like PolΦ. Polλ promotes MMEJ in mammalian cells independently of essential nonhomologous end-joining factors LIG4/XRCC4 and Polq, which indicates a distinct Polλ-dependent MMEJ mechanism.

As CRISPR-based therapies enter the clinic, evaluation of safety remains a critical and active area of study. Here the authors use next generation sequencing to achieve high sequencing depth and demonstrate that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants.

DNAPKcs and its kinase activity are required for blunt DNA break end joining when the bridging factor XLF is weakened, but for homologous recombination and radiation resistance, the influence of DNAPKcs is not further enhanced with loss of XLF.

The CRISPR/Cas system has emerged as a powerful and versatile genome engineering tool. Here the authors couple Cas9 to effector protein Exonuclease III via coiled-coil mediated interactions, termed CCExo, leading to increased deletion sizes and enhanced gene knock-out efficiencies in cell lines, primary cells and in vivo.