Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress
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 p...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-09-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124720311669 |
| _version_ | 1817975538206113792 |
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| author | Lora Boteva Ryu-Suke Nozawa Catherine Naughton Kumiko Samejima William C. Earnshaw Nick Gilbert |
| author_facet | Lora Boteva Ryu-Suke Nozawa Catherine Naughton Kumiko Samejima William C. Earnshaw Nick Gilbert |
| author_sort | Lora Boteva |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T21:51:14Z |
| format | Article |
| id | doaj.art-bd191e3aabbf4a60bf450f5a8d71b639 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T21:51:14Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-bd191e3aabbf4a60bf450f5a8d71b6392022-12-22T02:28:25ZengElsevierCell Reports2211-12472020-09-013212108177Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication StressLora Boteva0Ryu-Suke Nozawa1Catherine Naughton2Kumiko Samejima3William C. Earnshaw4Nick Gilbert5MRC Human Genetics Unit, The University of Edinburgh, Crewe Rd South, Edinburgh EH4 2XU, UKMRC Human Genetics Unit, The University of Edinburgh, Crewe Rd South, Edinburgh EH4 2XU, UKMRC Human Genetics Unit, The University of Edinburgh, Crewe Rd South, Edinburgh EH4 2XU, UKWellcome Centre for Cell Biology, The University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, UKWellcome Centre for Cell Biology, The University of Edinburgh, Michael Swann Building, Max Born Crescent, Edinburgh EH9 3BF, UKMRC Human Genetics Unit, The University of Edinburgh, Crewe Rd South, Edinburgh EH4 2XU, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124720311669chromosomechromatincondensinreplicationreplication stressgenome stability |
| spellingShingle | Lora Boteva Ryu-Suke Nozawa Catherine Naughton Kumiko Samejima William C. Earnshaw Nick Gilbert Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress Cell Reports chromosome chromatin condensin replication replication stress genome stability |
| title | Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress |
| title_full | Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress |
| title_fullStr | Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress |
| title_full_unstemmed | Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress |
| title_short | Common Fragile Sites Are Characterized by Faulty Condensin Loading after Replication Stress |
| title_sort | common fragile sites are characterized by faulty condensin loading after replication stress |
| topic | chromosome chromatin condensin replication replication stress genome stability |
| url | http://www.sciencedirect.com/science/article/pii/S2211124720311669 |
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