Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression

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 hu...

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Detalles Bibliográficos
Autores: Pérez Lorite, Neus, Apostolova, Sonia, Guasch Vallés, Marta, Pryer, Aaron, Unzueta, Fernando, Freire, Raimundo, Solé-Soler, Roger, Pedraza González, Neus, Dolcet Roca, Xavier, Garí Marsol, Eloi, Agell, Neus, Taylor, Elaine M., Colomina i Gabarrella, Neus, Torres Rosell, Jordi
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Universitat de Lleida (UdL)
Repositorio:Repositori Obert UdL
OAI Identifier:oai:repositori.udl.cat:10459.1/466302
Acceso en línea:https://doi.org/10.1007/s00018-024-05275-3
https://hdl.handle.net/10459.1/466302
Access Level:acceso abierto
Palabra clave:DNA replication
Genomic stability
NSE1
Smc5/6
SMC5
SMC6
NSE2
NSE3
NSE4
FANCM
RING
DNA fiber
MMS
Anaphase
Fanconi anemia
Descripción
Sumario: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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