1. Repression of Transcription at DNA Breaks Requires Cohesin throughout Interphase and Prevents Genome Instability.
- Author
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Meisenberg C, Pinder SI, Hopkins SR, Wooller SK, Benstead-Hume G, Pearl FMG, Jeggo PA, and Downs JA
- Subjects
- Antigens, Nuclear genetics, Antigens, Nuclear metabolism, Bone Neoplasms metabolism, Bone Neoplasms pathology, Cell Cycle Proteins metabolism, Cell Line, Tumor, Chromosomal Proteins, Non-Histone metabolism, Chromosome Segregation, DNA Repair, Down-Regulation, G1 Phase, G2 Phase, Gene Expression Regulation, Neoplastic, Humans, Osteosarcoma metabolism, Osteosarcoma pathology, Signal Transduction, Transcription Factors genetics, Transcription Factors metabolism, Cohesins, Bone Neoplasms genetics, Cell Cycle Proteins genetics, Chromosomal Proteins, Non-Histone genetics, DNA Breaks, Double-Stranded, Genomic Instability, Interphase, Osteosarcoma genetics, Transcription, Genetic
- Abstract
Cohesin subunits are frequently mutated in cancer, but how they function as tumor suppressors is unknown. Cohesin mediates sister chromatid cohesion, but this is not always perturbed in cancer cells. Here, we identify a previously unknown role for cohesin. We find that cohesin is required to repress transcription at DNA double-strand breaks (DSBs). Notably, cohesin represses transcription at DSBs throughout interphase, indicating that this is distinct from its known role in mediating DNA repair through sister chromatid cohesion. We identified a cancer-associated SA2 mutation that supports sister chromatid cohesion but is unable to repress transcription at DSBs. We further show that failure to repress transcription at DSBs leads to large-scale genome rearrangements. Cancer samples lacking SA2 display mutational patterns consistent with loss of this pathway. These findings uncover a new function for cohesin that provides insights into its frequent loss in cancer., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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