RT Journal Article SR Electronic T1 Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.07.25.453647 DO 10.1101/2021.07.25.453647 A1 Silvia Peripolli A1 Tanya Singh A1 Harshil Patel A1 Leticia Meneguello A1 Koshiro Kiso A1 Peter Thorpe A1 Cosetta Bertoli A1 Robertus A.M. de Bruin YR 2021 UL http://biorxiv.org/content/early/2021/07/26/2021.07.25.453647.abstract AB Oncogene-induced replication stress is a major driver of genomic instability in cancer cells, with a central role in both cancer initiation and progression (1). Despite its critical role in cancer development, the mechanisms that lay at the basis of oncogene-induced replication stress remains poorly understood. Here, we investigate the mechanism of c-Myc-induced replication stress. Our data shows that c-Myc induces replication stress by increasing the amount of cohesins bound to chromatin in the G1 phase of the cell cycle. This is independent of previously suggested mechanisms involving deregulation of replication initiation and transcriptional interference. Restoring the amount of chromatin-bound cohesins to control levels, or preventing the accumulation of cohesins at CTCF sites, in cells experiencing oncogenic c-Myc activity prevents replication stress. Increased cohesins chromatin occupancy correlates with a c-Myc-dependent increase in the levels of the cohesion loader Mau2. Preventing c-Myc-induced increase in Mau2 reduces oncogene-induced replication stress. Together our data support a novel mechanism for oncogene-induced replication stress. Since c-Myc activation is a crucial event in many human cancers (2), identifying the mechanisms through which this oncogene promotes replication stress provides critical insights into cancer biology.Competing Interest StatementThe authors have declared no competing interest.