Super-resolution visualization of distinct stalled and broken replication fork structures

Autoři: Donna R. Whelan aff001;  Wei Ting C. Lee aff002;  Frances Marks aff002;  Yu Tina Kong aff002;  Yandong Yin aff002;  Eli Rothenberg aff002
Působiště autorů: Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, Victoria, Australia aff001;  Department of Biochemistry and Molecular Pharmacology, Perlmutter Cancer Center, New York University School of Medicine, New York, New York, United States of America aff002
Vyšlo v časopise: Super-resolution visualization of distinct stalled and broken replication fork structures. PLoS Genet 16(12): e1009256. doi:10.1371/journal.pgen.1009256
Kategorie: Research Article


Endogenous genotoxic stress occurs in healthy cells due to competition between DNA replication machinery, and transcription and topographic relaxation processes. This causes replication fork stalling and regression, which can further collapse to form single-ended double strand breaks (seDSBs). Super-resolution microscopy has made it possible to directly observe replication stress and DNA damage inside cells, however new approaches to sample preparation and analysis are required. Here we develop and apply multicolor single molecule microscopy to visualize individual replication forks under mild stress from the trapping of Topoisomerase I cleavage complexes, a damage induction which closely mimics endogenous replicative stress. We observe RAD51 and RAD52, alongside RECQ1, as the first responder proteins to stalled but unbroken forks, whereas Ku and MRE11 are initially recruited to seDSBs. By implementing novel super-resolution imaging assays, we are thus able to discern closely related replication fork stress motifs and their repair pathways.

Klíčová slova:

DNA damage – DNA repair – DNA replication – Fluorescence imaging – In vivo imaging – Monte Carlo method – Non-homologous end joining – Recombinase polymerase amplification


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