Crucial Role of the NSE1 RING Domain in Smc5/6 Stability and FANCM-independent Fork Progression

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2024 Jun 7

PMID 38847937

Authors

Neus P Lorite

Sonia Apostolova

Marta Guasch-Valles

Aaron Pryer

Fernando Unzueta

Raimundo Freire

Roger Sole-Soler

Neus Pedraza

Xavier Dolcet

Eloi Gari

Neus Agell

Elaine M Taylor

Neus Colomina

Jordi Torres-Rosell

Affiliations

Soon will be listed here.

Abstract

The Smc5/6 complex is a highly conserved molecular machine involved in the maintenance of genome integrity. While its functions largely depend on restraining the fork remodeling activity of Mph1 in yeast, the presence of an analogous Smc5/6-FANCM regulation in humans remains unknown. We generated human cell lines harboring mutations in the NSE1 subunit of the Smc5/6 complex. Point mutations or truncations in the RING domain of NSE1 result in drastically reduced Smc5/6 protein levels, with differential contribution of the two zinc-coordinating centers in the RING. In addition, nse1-RING mutant cells display cell growth defects, reduced replication fork rates, and increased genomic instability. Notably, our findings uncover a synthetic sick interaction between Smc5/6 and FANCM and show that Smc5/6 controls fork progression and chromosome disjunction in a FANCM-independent manner. Overall, our study demonstrates that the NSE1 RING domain plays vital roles in Smc5/6 complex stability and fork progression through pathways that are not evolutionary conserved.

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