Oncogenic C-Myc Induces Replication Stress by Increasing Cohesins Chromatin Occupancy in a CTCF-dependent Manner

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Feb 21

PMID 38383676

Authors

Silvia Peripolli

Leticia Meneguello

Chiara Perrod

Tanya Singh

Harshil Patel

Sazia T Rahman

Koshiro Kiso

Peter Thorpe

Vincenzo Calvanese

Cosetta Bertoli

Robertus A M de Bruin

Affiliations

Soon will be listed here.

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.

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