Perturbation on DNA replication by cohesin dysfunction leads to gross genomic damages [END-seq]

ABSTRACT: Cohesin loss-of-function mutations are frequently observed in tumors, but the mechanism is unclear. Here, we found that depletion of RAD21, a core subunit of cohesin, leads to massive DNA breaks, up to five-fold, and 147 translocation hotspot genes that are co-mutated with cohesin in multiple cancers. DNA damages are independent of RAD21-loss-induced transcription alteration and loop anchor elimination. However, translocation junctions coincide with the asymmetrically distributed Okazaki fragments of DNA replication, suggesting that RAD21 depletion causes replication stresses evidenced by the slower replication speed and increased stalled forks. Mechanistically, approximately 30% of the human genome exhibits an earlier replication timing after RAD21 depletion, caused by the early initiation of >900 extra dormant origins. Correspondingly, most translocation hotspot genes lie in timing-altered regions. Therefore, we conclude that cohesin dysfunction causes severe replication stresses induced by extra DNA replication, resulting in gross DNA damages that may induce tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211343 | GEO | 2023/05/18

REPOSITORIES: GEO