Oncogenic C-Myc Induces Replication Stress by Increasing Cohesins Chromatin Occupancy at Ctcf Sites

Abstract

Oncogene-induced replication stress is a major driver of genomic instability in cancer cells, with a central role in both cancer initiation and progression (Gorgoulis, Vassiliou et al. 2005). 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 before S phase entry. Restoring the amount of chromatin-bound cohesins to control levels in cells experiencing oncogenic c-Myc prevents replication stress. Specifically preventing accumulation of cohesins at CTCF sites, by CTCF depletion, without reducing the levels of chromatin-bound cohesins, prevents c-Myc-induced replication stress. This indicates that increased cohesins accumulation at CTCF sites contributes to c-Myc-induced replication fork slowing. The increase in cohesins chromatin occupancy correlates with a c-Myc-dependent induction of the cohesion loader Mau2 and preventing the Mau2 induction reduces replication stress levels.Together our data support an important role for cohesins in causing oncogene-induced replication stress, in addition to their role in replication stress-induced DNA damage repair. Since c-Myc activation is a crucial event in many human cancers (Dang 2012), identifying the mechanisms through which this oncogene promotes replication stress provides critical insights into cancer biology.

Keywords: Oncogene-induced replication stress, c-Myc, cell cycle, cohesins, cancer, DNA damage, DNA replication