Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress

Cell Reports

Ryu-Suke Nozawa¹  Lora Boteva¹  Nick Gilbert¹  Catherine Naughton¹  William C. Earnshaw²  Kumiko Samejima² 

[1] MRC Human Genetics Unit, The University of Edinburgh, Crewe Rd South, Edinburgh EH4 2XU, UK;Wellcome Centre for Cell Biology, The University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, UK;

关键词: chromosome;    chromatin;    condensin;    replication;    replication stress;    genome stability;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Cells coordinate interphase-to-mitosis transition, but recurrent cytogenetic lesions appear at common fragile sites (CFSs), termed CFS expression, in a tissue-specific manner after replication stress, marking regions of instability in cancer. Despite such a distinct defect, no model fully provides a molecular explanation for CFSs. We show that CFSs are characterized by impaired chromatin folding, manifesting as disrupted mitotic structures visible with molecular fluorescence in situ hybridization (FISH) probes in the presence and absence of replication stress. Chromosome condensation assays reveal that compaction-resistant chromatin lesions persist at CFSs throughout the cell cycle and mitosis. Cytogenetic and molecular lesions are marked by faulty condensin loading at CFSs, a defect in condensin-I-mediated compaction, and are coincident with mitotic DNA synthesis (MIDAS). This model suggests that, in conditions of exogenous replication stress, aberrant condensin loading leads to molecular defects and CFS expression, concomitantly providing an environment for MIDAS, which, if not resolved, results in chromosome instability.

【 授权许可】

Unknown