Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy in a CTCF-dependent manner

Silvia Peripolli, Leticia Meneguello, Chiara Perrod, Tanya Singh, Harshil Patel, Sazia T. Rahman, Koshiro Kiso, Peter Thorpe, Vincenzo Calvanese, Cosetta Bertoli () and Robertus A. M. de Bruin ()
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Silvia Peripolli: University College London
Leticia Meneguello: University College London
Chiara Perrod: University College London
Tanya Singh: University College London
Harshil Patel: Francis Crick Institute
Sazia T. Rahman: University College London
Koshiro Kiso: University College London
Peter Thorpe: Queen Mary University
Vincenzo Calvanese: University College London
Cosetta Bertoli: University College London
Robertus A. M. de Bruin: University College London

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Oncogene-induced replication stress is a crucial driver of genomic instability and one of the key events contributing to the onset and evolution of cancer. Despite its critical role in cancer, the mechanisms that generate oncogene-induced replication stress remain not fully understood. Here, we report that an oncogenic c-Myc-dependent increase in cohesins on DNA contributes to the induction of replication stress. Accumulation of cohesins on chromatin is not sufficient to cause replication stress, but also requires cohesins to accumulate at specific sites in a CTCF-dependent manner. We propose that the increased accumulation of cohesins at CTCF site interferes with the progression of replication forks, contributing to oncogene-induced replication stress. This is different from, and independent of, previously suggested mechanisms of oncogene-induced replication stress. This, together with the reported protective role of cohesins in preventing replication stress-induced DNA damage, supports a double-edge involvement of cohesins in causing and tolerating oncogene-induced replication stress.

Date: 2024
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DOI: 10.1038/s41467-024-45955-z

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