DNA double strand breaks (DSBs) need to be rapidly repaired to avoid cell death and genomic instability. Efficient repair of DSBs relies on a complex signalling cascade coupled with the local remodelling of chromatin and the recruitment of repair effector mechanisms. At the heart of DNA damage signalling lie the phosphatidylinositol-3-kinase-like kinase (PIKK) family, DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia-mutated (ATM), and ataxia telangiectasia-mutated related (ATR). ATR and ATM respond primarily to replication fork arrest and S phase DSBs, while DNA-PK is best known for its role in promoting non-homologous end joining. Lu et al. show that the catalytic activity of DNA-PK, which reaches DSBs more quickly than the other PIKKs, is responsible for phosphorylating the histone H2AX and chromatin remodeller KAP1 and, in turn, these DNA-PK-dependent phosphorylations promote very early chromatin relaxation around the break and recruitment of repair proteins.
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.
The maintenance of telomere length is critical to longevity and survival. The failure to properly replicate, resect, and/or form appropriate telomeric structures drives telomere shortening and genomic instability. The endonuclease CtIP is a DNA repair protein that is well-known to promote genome stability through the resection of endogenous DNA double-stranded breaks. Here, the authors show that in the absence of CtIP, human telomeres shorten rapidly to non-viable lengths. This telomere dysfunction results in an accumulation of fusions, breaks, and frank telomere loss. Additionally, CtIP suppresses the generation of circular, extrachromosomal telomeric DNA. These latter structures appear to arise from arrested DNA replication forks that accumulate in the absence of CtIP. Hence, CtIP is required for faithful replication through telomeres via its roles at stalled replication tracts. These findings demonstrate a new role for CtIP as a protector of human telomere integrity.
Nucleotide excision repair (NER) is a highly conserved DNA repair pathway in charge of eliminating a diverse repertoire of DNA damages. Xeroderma pigmentosum complementation group C protein (XPC) along with RAD23B and Centrin2, recognizes a variety of NER substrates by sensing the local distortion and/or thermodynamic destabilization of the DNA helix caused by the modified bases. In this study, the authors have visualized the movement of human NER protein XPC-RAD23B on DNA using DNA curtains, a novel single-molecule real-time imaging technique. The study elucidates the motion of the protein complex on damaged and undamaged DNA and provides important insights into how XPC-RAD23B initiates NER. The complex displayed multiple types of motions - with constrained localization of the repair machinery highly correlated with AT-tracks, suggesting that local DNA instability plays a role in the lesion search process.
