53BP1 Protects against CtIP-Dependent Capture of Ectopic Chromosomal Sequences at the Junction of Distant Double-Strand Breaks

• DOI: 10.1371/journal.pgen.1006230
• Publication Date: 2016-10-31T13:35:32Z
• Authors: Josée Guirouilh-B...; Camille Gelot; Anyong Xie; Elodie Dardillac; Ralph Scully; Bernard S. Lopez
• Keywords: DNA End-Joining Repair; QH426-470; Biochemistry; Medicine and Health Sciences; Small interfering RNAs; DNA Breaks, Double-Stranded; Cell Cycle and Cell Division; Recombination, Genetic; 0303 health sciences; Chromosome Biology; Sequence analysis; Nuclear Proteins; Genomics; Nucleic acids; Meiosis; Cell Processes; Tumor Suppressor p53-Binding Protein 1; Research Article; 570; Nucleotide Sequencing; 610; DNA, Single-Stranded; Surgical and Invasive Medical Procedures; [SDV.CAN]Life Sciences [q-bio]/Cancer; DNA replication; Genome Complexity; Chromosomes; 03 medical and health sciences; Genetics; Humans; Gene Silencing; Molecular Biology Techniques; Sequencing Techniques; Non-coding RNA; Molecular Biology; DNA sequence analysis; Endodeoxyribonucleases; Surgical Resection; Genome, Human; Biology and Life Sciences; Computational Biology; Cell Biology; Synapsis; DNA; Fibroblasts; Gene regulation; Chromosome Pairing; [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics; RNA; Gene expression; Carrier Proteins

DNA double-strand breaks (DSB) are very harmful lesions that can generate genome rearrangements. In this study, we used intrachromosomal reporters to compare both the efficiency and accuracy of end-joining occurring with close (34 bp apart) vs. distant DSBs (3200 in human fibroblasts. We showed a few kb between two I-SceI-induced sufficient foster deletions capture/insertions at junction scar. Captured sequences mostly coupled be partial duplications reporter (i.e., adjacent DSB) or insertions ectopic chromosomal (ECS). Interestingly, silencing 53BP1 stimulates but not ends (DSEs), although were stimulated case. This shows protects DSEs from degradation association unprotection distance favors ECS capture. Reciprocally, CtIP lessens capture control 53BP1-depleted cells. propose immediately/rapidly tethered ligated, whereas first require synapsis prior ligation. "spatio-temporal" gap gives time space for initiate resection, suggesting an involvement single-stranded tails therefore speculate resulting copies through microhomology-mediated template switching.