Repression of Transcription at DNA Breaks Requires Cohesin throughout Interphase and Prevents Genome Instability.
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Date
2019-01-17Author
Meisenberg, C
Pinder, SI
Hopkins, SR
Wooller, SK
Benstead-Hume, G
Pearl, FMG
Jeggo, PA
Downs, JA
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line, Tumor
Humans
Osteosarcoma
Bone Neoplasms
Genomic Instability
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
Antigens, Nuclear
Transcription Factors
Signal Transduction
Chromosome Segregation
Interphase
G1 Phase
G2 Phase
DNA Repair
Transcription, Genetic
Down-Regulation
Gene Expression Regulation, Neoplastic
DNA Breaks, Double-Stranded
Research team
Epigenetics and Genome Stability
Language
eng
Date accepted
2018-11-01
License start date
2019-01
Citation
Molecular cell, 2019, 73 (2), pp. 212 - 223.e7
Publisher
CELL PRESS