iScience (Sep 2023)

Developing a peptide to disrupt cohesin head domain interactions

  • Maria Elias,
  • Samar Gani,
  • Yana Lerner,
  • Katreen Yamin,
  • Chen Tor,
  • Adarsh Patel,
  • Avi Matityahu,
  • Moshe Dessau,
  • Nir Qvit,
  • Itay Onn

Journal volume & issue
Vol. 26, no. 9
p. 107498

Abstract

Read online

Summary: Cohesin mediates the 3-D structure of chromatin and is involved in maintaining genome stability and function. The cohesin core comprises Smc1 and Smc3, elongated-shaped proteins that dimerize through globular domains at their edges, called head and hinge. ATP binding to the Smc heads induces their dimerization and the formation of two active sites, while ATP hydrolysis results in head disengagement. This ATPase cycle is essential for driving cohesin activity. We report on the development of the first cohesin-inhibiting peptide (CIP). The CIP binds Smc3 in vitro and inhibits the ATPase activity of the holocomplex. Treating yeast cells with the CIP prevents cohesin’s tethering activity and, interestingly, leads to the accumulation of cohesin on chromatin. CIP3 also affects cohesin activity in human cells. Altogether, we demonstrate the power of peptides to inhibit cohesin in cells and discuss the potential application of CIPs as a therapeutic approach.

Keywords