GSE211346
Perturbation on DNA replication by cohesin dysfunction leads to gross genomic damages [NAIL-seq mES-EdUHU]
Cohesin 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 gross DNA breaks and consequently elevates genome-wide chromosomal translocation levels up to five-fold in mammalian cells. These damages are independent of transcription alteration and loop anchor robustness. However, identified translocations occur asymmetrically on the chromatin Watson and Crick strands, coincident with Okazaki fragments of DNA replication. Moreover, early DNA replication initiates at about one thousand extra dormant origins after RAD21 depletion, which is independent of CTCF, resulting in earlier replicating timing at approximately 30% or 13% of the human or mouse genomic regions, respectively. And the translocation hotspot genes arising in RAD21-depleted cells are accompanied by dysregulated replication timing. Therefore, we conclude that cohesin dysfunction leads to perturbed DNA replication timing, which further results in gross DNA damages that may be involved in tumorigenesis. Overall design: We applied NAIL-seq to identify the early replication initiation zones in mES RAD21-depleted cells.